Muscarinic agonists

ABSTRACT

or a salt thereof, wherein q, r, s, Q, R1, R2′, R2″, R3 and R4 are as defined herein.

This application is a continuation of U.S. patent application Ser. No.15/749,957, filed Feb. 2, 2018, which is a 371 U.S. national phase ofInternational Patent Application No.: PCT/GB2016/052385, filed Aug. 3,2016, which claims priority to GB Application No.: 1513743.3, filed Aug.3, 2015, all of which are incorporated herein by reference in theirentirety.

This invention relates to compounds that are agonists of the muscarinicM₁ receptor and/or M₄ receptor and which are useful in the treatment ofmuscarinic M₁/M₄ receptor mediated diseases. Also provided arepharmaceutical compositions containing the compounds and the therapeuticuses of the compounds.

BACKGROUND OF THE INVENTION

Muscarinic acetylcholine receptors (mAChRs) are members of the Gprotein-coupled receptor superfamily which mediate the actions of theneurotransmitter acetylcholine in both the central and peripheralnervous system. Five mAChR subtypes have been cloned, M₁ to M₅. The M₁mAChR is predominantly expressed post-synaptically in the cortex,hippocampus, striatum and thalamus; M₂ mAChRs are located predominantlyin the brainstem and thalamus, though also in the cortex, hippocampusand striatum where they reside on cholinergic synaptic terminals(Langmead et al., 2008 Br J Pharmacol). However, M₂ mAChRs are alsoexpressed peripherally on cardiac tissue (where they mediate the vagalinnervation of the heart) and in smooth muscle and exocrine glands. M₃mAChRs are expressed at relatively low level in the CNS but are widelyexpressed in smooth muscle and glandular tissues such as sweat andsalivary glands (Langmead et al., 2008 Br J Pharmacol).

Muscarinic receptors in the central nervous system, especially the M₁mAChR, play a critical role in mediating higher cognitive processing.Diseases associated with cognitive impairments, such as Alzheimer'sdisease, are accompanied by loss of cholinergic neurons in the basalforebrain (Whitehouse et al., 1982 Science). In schizophrenia, whichalso has cognitive impairment as an important component of the clinicalpicture, mAChR density is reduced in the pre-frontal cortex, hippocampusand caudate putamen of schizophrenic subjects (Dean et al., 2002 MolPsychiatry). Furthermore, in animal models, blockade or damage tocentral cholinergic pathways results in profound cognitive deficits andnon-selective mAChR antagonists have been shown to inducepsychotomimetic effects in psychiatric patients. Cholinergic replacementtherapy has largely been based on the use of acetylcholinesteraseinhibitors to prevent the breakdown of endogenous acetylcholine. Thesecompounds have shown efficacy versus symptomatic cognitive decline inthe clinic, but give rise to dose-limiting adverse events resulting fromstimulation of peripheral M₂ and M₃ mAChRs including disturbedgastrointestinal motility, bradycardia, nausea and vomiting(www.drugs.com/pro/donepezil.html; www.drugs.com/pro/rivastigmine.html).

Further discovery efforts have targeted the identification of direct M₁mAChR agonists with the aim of inducing selective improvements incognitive function with a favourable adverse effect profile. Suchefforts resulted in the identification of a range of agonists,exemplified by compounds such as xanomeline, AF267B, sabcomeline,milameline and cevimeline. Many of these compounds have been shown to behighly effective in pre-clinical models of cognition in both rodentsand/or non-human primates. Milameline has shown efficacy versusscopolamine-induced deficits in working and spatial memory in rodents;sabcomeline displayed efficacy in a visual object discrimination task inmarmosets and xanomeline reversed mAChR antagonist-induced deficits incognitive performance in a passive avoidance paradigm.

Alzheimer's disease (AD) is the most common neurodegenerative disorder(26.6 million people worldwide in 2006) that affects the elderly,resulting in profound memory loss and cognitive dysfunction. Theaetiology of the disease is complex, but is characterised by twohallmark brain pathologies: aggregates of amyloid plaques, largelycomposed of amyloid-β peptide (Aβ), and neurofibrillary tangles, formedby hyperphosphorylated tau proteins. The accumulation of Aβ is thoughtto be the central feature in the progression of AD and, as such, manyputative therapies for the treatment of AD are currently targetinginhibition of Aβ production. Aβ is derived from proteolytic cleavage ofthe membrane bound amyloid precursor protein (APP). APP is processed bytwo routes, nonamyloidgenic and amyloidgenic. Cleavage of APP byγ-secretase is common to both pathways, but in the former APP is cleavedby an α-secretase to yield soluble APPα. However, in the amyloidgenicroute, APP is cleaved by β-secretase to yield soluble APPβ and also Aβ.In vitro studies have shown that mAChR agonists can promote theprocessing of APP toward the soluble, non-amyloidogenic pathway. In vivostudies showed that the mAChR agonist, AF267B, altered disease-likepathology in the 3×TgAD transgenic mouse, a model of the differentcomponents of Alzheimer's disease (Caccamo et al., 2006 Neuron). ThemAChR agonist cevimeline has been shown to give a small, butsignificant, reduction in cerebrospinal fluid levels of Aβ inAlzheimer's patients, thus demonstrating potential disease modifyingefficacy (Nitsch et al., 2000 Neurol).

Preclinical studies have suggested that mAChR agonists display anatypical antipsychotic-like profile in a range of pre-clinicalparadigms. The mAChR agonist, xanomeline, reverses a number of dopaminemediated behaviours, including amphetamine induced locomotion in rats,apomorphine induced climbing in mice, dopamine agonist driven turning inunilateral 6-OH-DA lesioned rats and amphetamine induced motor unrest inmonkeys (without EPS liability). It also has been shown to inhibit A10,but not A9, dopamine cell firing and conditioned avoidance and inducesc-fos expression in prefrontal cortex and nucleus accumbens, but not instriatum in rats. These data are all suggestive of an atypicalantipsychotic-like profile (Mirza et al., 1999 CNS Drug Rev). Muscarinicreceptors have also been implicated in the neurobiology of addiction.The reinforcing effects of cocaine and other addictive substances aremediated by the mesolimbic dopamine system where behavioral andneurochemical studies have shown that the cholinergic muscarinicreceptor subtypes play important roles in regulation of dopaminergicneurotransmission. For example M(4) (−/−) mice demonstratedsignificantly enhanced reward driven behaviour as result of exposure tococaine (Schmidt et al Psychopharmacology (2011) August; 216(3):367-78).Furthermore xanomeline has been demonstrated to block the effects ofcocaine in these models.

Muscarinic receptors are also involved in the control of movement andpotentially represent novel treatments for movement disorders such asParkinson's disease, ADHD, Huntingdon's disease, tourette's syndrome andother syndromes associated with dopaminergic dysfunction as anunderlying pathogenetic factor driving disease.

Xanomeline, sabcomeline, milameline and cevimeline have all progressedinto various stages of clinical development for the treatment ofAlzheimer's disease and/or schizophrenia. Phase II clinical studies withxanomeline demonstrated its efficacy versus various cognitive symptomdomains, including behavioural disturbances and hallucinationsassociated with Alzheimer's disease (Bodick et al., 1997 Arch Neurol).This compound was also assessed in a small Phase I study ofschizophrenics and gave a significant reduction in positive and negativesymptoms when compared to placebo control (Shekhar et al., 2008 Am JPsych). However, in all clinical studies xanomeline and other relatedmAChR agonists have displayed an unacceptable safety margin with respectto cholinergic adverse events, including nausea, gastrointestinal pain,diahorrhea, diaphoresis (excessive sweating), hypersalivation (excessivesalivation), syncope and bradycardia.

Muscarinic receptors are involved in central and peripheral pain. Paincan be divided into three different types: acute, inflammatory, andneuropathic. Acute pain serves an important protective function inkeeping the organism safe from stimuli that may produce tissue damage;however management of post-surgical pain is required. Inflammatory painmay occur for many reasons including tissue damage, autoimmune response,and pathogen invasion and is triggered by the action of inflammatorymediators such as neuropeptides and prostaglandins which result inneuronal inflammation and pain. Neuropathic pain is associated withabnormal painful sensations to non-painful stimuli. Neuropathic pain isassociated with a number of different diseases/traumas such as spinalcord injury, multiple sclerosis, diabetes (diabetic neuropathy), viralinfection (such as HIV or Herpes). It is also common in cancer both as aresult of the disease or a side effect of chemotherapy. Activation ofmuscarinic receptors has been shown to be analgesic across a number ofpain states through the activation of receptors in the spinal cord andhigher pain centres in the brain. Increasing endogenous levels ofacetylcholine through acetylcholinesterase inhibitors, direct activationof muscarinic receptors with agonists or allosteric modulators has beenshown to have analgesic activity. In contrast blockade of muscarinicreceptors with antagonists or using knockout mice increases painsensitivity. Evidence for the role of the M₁ receptor in pain isreviewed by D. F. Fiorino and M. Garcia-Guzman, 2012.

More recently, a small number of compounds have been identified whichdisplay improved selectivity for the M₁ mAChR subtype over theperipherally expressed mAChR subtypes (Bridges et al., 2008 Bioorg MedChem Lett; Johnson et al., 2010 Bioorg Med Chem Lett; Budzik et al.,2010 ACS Med Chem Lett). Despite increased levels of selectivity versusthe M₃ mAChR subtype, some of these compounds retain significant agonistactivity at both this subtype and the M₂ mAChR subtype. Herein wedescribe a series of compounds which unexpectedly display high levels ofselectivity for the M₁ and/or M₄ mAChR over the M₂ and M₃ receptorsubtypes.

The Invention

The present invention provides compounds having activity as muscarinicM₁ and/or M₄ receptor agonists. More particularly, the inventionprovides compounds that exhibit selectivity for the M₁ receptor and/orthe M₄ receptor relative to the M₂ and M₃ receptor subtypes.

Accordingly, in one embodiment (Embodiment 1.1), the invention providesa compound of the formula (1):

or a salt thereof, wherein

q is 0, 1 or 2;

r is 1 or 2;

s is 0 or 1 where the total of r and s is 1 or 2;

Q is a four membered ring containing 0 or 1 nitrogen atoms;

R¹ is selected from hydrogen; fluorine; chlorine; bromine; cyano; oxo;hydroxy; OR⁵; NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NRCOR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶;NR⁷COOR⁵; OCONR⁵R⁶; SR⁵; SOR⁵ and SO₂R⁵; a C₁₋₆ non-aromatic hydrocarbongroup which is optionally substituted with one to six fluorine atoms andwherein one or two, but not all, carbon atoms of the hydrocarbon groupmay optionally be replaced by a heteroatom selected from O, N and S andoxidized forms thereof; and an optionally substituted 5- or 6-memberedring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S andoxidized forms thereof;

R^(2′) and R^(2″) are independently selected from hydrogen; fluorine;chlorine; bromine; cyano; hydroxy; methoxy; OR⁵; NR⁵R⁶; COR⁵; COOR⁵;OCOR⁵; NRCOR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶; NR⁷COR⁵; OCONR⁵R⁶; SR⁵; SOR⁵ andSO₂R⁵; a C₁₋₆ non-aromatic hydrocarbon group; or R¹ and R^(2′) can bejoined together to form a 4-7 membered fused ring;

R³ is selected from hydrogen; fluorine; cyano; hydroxy; amino; and aC₁₋₉ non-aromatic hydrocarbon group which is optionally substituted withone to six fluorine atoms and wherein one, two or three, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidized forms thereof;

R⁴ is a hydrogen or a C₁₋₆ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one ortwo, but not all, carbon atoms of the hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidised formsthereof;

R⁵, R⁶ and R⁷ are the same or different and each is independentlyselected from hydrogen, a non-aromatic C₁₋₄ hydrocarbon group optionallysubstituted with one or more fluorine atoms; or a group of formulaCH₂N(R^(a))COOR^(b);

R^(a) is selected from hydrogen and a non-aromatic C₁₋₄ hydrocarbongroup;

R^(b) is a non-aromatic C₁₋₄ hydrocarbon group which is optionallysubstituted with one or more groups selected from fluorine; chlorine;bromine; cyano; hydroxy; methoxy; amino; or a cycloalkyl,heterocycloalkyl, aryl or heteroaryl group;

and the dotted line indicates an optional second carbon-carbon bond,provided that when a second carbon-carbon bond is present, then R³ isabsent.

Particular compounds of the formula (1) are as defined in theEmbodiments 1.2 to 1.104 set out below.

1.2 A compound according to Embodiment 1.1 wherein Q is an azetidinering.

1.3 A compound according to Embodiment 1.1 wherein Q is a cyclobutylring.

1.4 A compound according to Embodiment 1.2 wherein Q is an azetidinering linked to the adjacent five-membered, six-membered or sevenmembered ring by a carbon atom of the azetidine ring.

1.5 A compound according to Embodiment 1.2 wherein Q is an azetidinering linked to the adjacent five-membered, six-membered or sevenmembered ring by the nitrogen atom of the azetidine ring.

1.6 A compound according to Embodiments 1.1 to 1.5 wherein Q isbicyclic; having a further ring attached to Q.

1.7 A compound according to any one of Embodiments 1.1 to 1.6 wherein R¹is selected from hydrogen; fluorine; chlorine; bromine; cyano; oxo;hydroxy; OR⁵; NR⁵R⁶; COR⁵, COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶;NR⁷COOR⁵; OCONR⁵R⁶; SR⁵; SOR⁵ and SO₂R⁵; a C₁₋₆ non-aromatic hydrocarbongroup which is optionally substituted with one to six fluorine atoms andwherein one or two, but not all, carbon atoms of the hydrocarbon groupmay optionally be replaced by a heteroatom selected from O, N and S andoxidized forms thereof; and an optionally substituted 5- or 6-memberedring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S andoxidized forms thereof;

-   -   wherein the optional substituents for the optionally substituted        5- or 6-membered ring are selected from a group R⁸ consisting of        hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR⁵;        NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶;        NR⁷COOR⁵; OCONR⁵R⁶; SR⁵; SOR⁵ and SO₂R⁵; and a C₁₋₆ non-aromatic        hydrocarbon group which is optionally substituted with one to        six fluorine atoms and wherein one or two, but not all, carbon        atoms of the hydrocarbon group may optionally be replaced by a        heteroatom selected from O, N and S and oxidized forms thereof.

1.8 A compound according to Embodiment 1.7 wherein R¹ is selected fromhydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR⁵; NR⁵R⁶;COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶; NR⁷COOR⁵; OCONR⁵R⁶;SR⁵; SOR⁵ and SO₂R⁵; a C₁₋₅ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one ortwo, but not all, carbon atoms of the hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidized formsthereof; and an optionally substituted 5- or 6-membered ring containing0, 1 or 2 heteroatoms selected from O, N and S and oxidized formsthereof;

-   -   wherein the optional substituents for the optionally substituted        5- or 6-membered ring are selected from a group R⁸ consisting of        fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR⁵; NR⁵R⁶;        COR⁵; COORS; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶; NR⁷COOR⁵;        OCONR⁵R⁶; SR⁵; SOR⁵ and SO₂R⁵; and a C₁₋₄ non-aromatic        hydrocarbon group which is optionally substituted with one to        six fluorine atoms and wherein one or two, but not all, carbon        atoms of the hydrocarbon group may optionally be replaced by a        heteroatom selected from O, N and S and oxidized forms thereof.

1.9 A compound according to Embodiment 1.8 wherein R¹ is selected fromhydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR⁵; NR⁵R⁶;COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶; NR⁷COOR⁵; OCONR⁵R⁶;SR⁵; SOR⁵ and SO₂R⁵; a C₁₋₄ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one ortwo, but not all, carbon atoms of the hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidized formsthereof; and an optionally substituted 5- or 6-membered aryl orheteroaryl ring containing 0, 1 or 2 heteroatoms selected from O, N andS and oxidized forms thereof;

-   -   wherein the optional substituents for the optionally substituted        5- or 6-membered aryl or heteroaryl ring are selected from a        group R consisting of fluorine; chlorine; bromine; cyano; oxo;        hydroxy; OR⁵; NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶;        NR⁷CONR⁵R⁶; NR⁷COOR⁵; OCONR⁵R⁶; SR⁵; SOR⁵ and SO₂R⁵; and a C₁₋₄        non-aromatic hydrocarbon group which is optionally substituted        with one to six fluorine atoms and wherein one or two, but not        all, carbon atoms of the hydrocarbon group may optionally be        replaced by a heteroatom selected from O, N and S and oxidized        forms thereof.

1.10 A compound according to any one of Embodiments 1.1 to 1.9 whereinR¹ is selected from hydrogen; fluorine; chlorine; cyano; oxo; hydroxy;OR⁵; NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶; NR⁷COOR⁵;OCONR⁵R⁶; SO₂R⁵; a C₁₋₄ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one ortwo, but not all, carbon atoms of the hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidized formsthereof; and an optionally substituted 5- or 6-membered ring containing0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized formsthereof, wherein the optional substituents for the optionallysubstituted 5- or 6-membered ring are selected from a group R⁸consisting of fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR⁵;NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶; NR⁷COOR⁵;OCONR⁵R⁶; SR⁵; SOR⁵ and SO₂R⁵; and a C₁₋₄ non-aromatic hydrocarbon groupwhich is optionally substituted with one to six fluorine atoms andwherein one or two, but not all, carbon atoms of the hydrocarbon groupmay optionally be replaced by a heteroatom selected from O, N and S andoxidized forms thereof.

1.11 A compound according to Embodiment 1.10 wherein R¹ is selected fromhydrogen; fluorine; chlorine; cyano; hydroxy; OR⁵; NR⁵R⁶; COR⁵; COOR⁵;OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶; NR⁷COOR⁵; OCONR⁵R⁶; SO₂R⁵; and aC₁₋₄ non-aromatic hydrocarbon group which is optionally substituted withone to six fluorine atoms and wherein one or two, but not all, carbonatoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidized forms thereof.

1.12 A compound according to Embodiment 1.11 wherein R¹ is selected fromhydrogen; fluorine; chlorine; cyano; hydroxy; OR⁵; NR⁵R⁶; COR⁵; COORS;OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶; NR⁷COOR⁵; SO₂R⁵; and a C₁₋₄non-aromatic hydrocarbon group which is optionally substituted with oneto six fluorine atoms.

1.13 A compound according to Embodiment 1.12 wherein R¹ is selected fromhydrogen; fluorine; chlorine; cyano; NR⁵R⁶; COR⁵; COOR⁵ and a C₁₋₆non-aromatic hydrocarbon group which is optionally substituted with oneto six fluorine atoms.

1.14 A compound according to Embodiment 1.13 wherein R¹ is selected fromhydrogen; fluorine; chlorine; cyano; NH₂, COR⁵; COOR⁵ and a C₁₋₄saturated non-aromatic hydrocarbon group which is optionally substitutedwith one to six fluorine atoms.

1.15 A compound according to Embodiment 1.14 wherein R¹ is selected fromhydrogen; COR⁵; COOR⁵; CONR⁵R⁶ and a C₁₋₄ alkyl group.

1.16 A compound according to Embodiment 1.15 wherein R¹ is selected fromhydrogen; COR⁵; COOR⁵ and a C₁₋₃ alkyl group.

1.17 A compound according to Embodiment 1.16 wherein R¹ is selected fromhydrogen; methyl; ethyl and COORS.

1.18 A compound according to Embodiment 1.17 wherein R¹ is hydrogen.

1.19 A compound according to Embodiment 1.17 wherein R¹ is methyl orethyl.

1.20 A compound according to Embodiment 1.7 to 1.17 wherein R¹ is COOMe;COOEt; COMe; COEt; CONH₂; CF₃; CONHMe; CON(Me)₂; COCF₃; CO-cyclopropyl;CO-cyclobutyl; CONHEt; COH; NH₂; OMe;

1.21 A compound according to any one of the Embodiments 1.1 to 1.20wherein R^(2′) is selected from hydrogen; fluorine; chlorine; bromine;cyano; hydroxy; methoxy; and a C₁₋₆ non-aromatic hydrocarbon group; oris joined together with R¹ to form a 6 membered fused aromatic ring.

1.22 A compound according to Embodiment 1.21 wherein R^(2′) is selectedfrom hydrogen; fluorine; hydroxy; methoxy; and a C₁₋₆ non-aromatichydrocarbon group.

1.23 A compound according to Embodiment 1.22 wherein R^(2′) is selectedfrom hydrogen; fluorine; methoxy; and a C₁₋₄ saturated hydrocarbongroup.

1.24 A compound according to Embodiment 1.23 wherein R^(2′) is selectedfrom hydrogen; fluorine; methoxy; and a C₁₋₄ alkyl group.

1.25 A compound according to Embodiment 1.24 wherein R^(2′) is selectedfrom hydrogen and a C₁₋₃ alkyl group.

1.26 A compound according to Embodiment 1.25 wherein R^(2′) is selectedfrom hydrogen and methyl.

1.27 A compound according to Embodiment 1.21 wherein R^(2′) is joinedtogether with R¹ to form a 4 to 7 membered fused ring.

1.28 A compound according to Embodiment 1.27 wherein R^(2′) is joinedtogether with R¹ to form a 5 or 6 membered fused aromatic ring which maybe aryl or heteroaryl.

1.29 A compound according to any one of the Embodiments 1.1 to 1.28wherein R^(2″) is selected from hydrogen; fluorine; chlorine; bromine;cyano; hydroxy; methoxy; and a C₁₋₆ non-aromatic hydrocarbon group; oris joined together with R¹ to form a 6 membered fused aromatic ring.

1.30 A compound according to Embodiment 1.29 wherein R^(2″) is selectedfrom hydrogen; fluorine; hydroxy; methoxy; and a C₁₋₆ non-aromatichydrocarbon group.

1.31 A compound according to Embodiment 1.30 wherein R^(2″) is selectedfrom hydrogen; fluorine; methoxy; and a C₁₋₄ saturated hydrocarbongroup.

1.32 A compound according to Embodiment 1.31 wherein R^(2″) is selectedfrom hydrogen; fluorine; methoxy; and a C₁₋₄ alkyl group.

1.33 A compound according to Embodiment 1.32 wherein R^(2″) is selectedfrom hydrogen and a C₁₋₃ alkyl group.

1.34 A compound according to Embodiment 1.33 wherein R^(2″) is selectedfrom hydrogen and methyl.

1.35 A compound according to any one of Embodiments 1.1 to 1.34 whereinthe dotted line represents a second carbon-carbon bond and R³ is absent.

1.36 A compound according to any one of Embodiments 1.1 to 1.34 whereinR³ is present and the optional second carbon-carbon bond is absent.

1.37 A compound according to Embodiment 1.36 wherein R³ is selected fromhydrogen; fluorine; cyano; hydroxy; amino; and a C₁₋₆ non-aromatichydrocarbon group which is optionally substituted with one to sixfluorine atoms and wherein one or two, but not all, carbon atoms of thehydrocarbon group may optionally be replaced by a heteroatom selectedfrom O, N and S and oxidized forms thereof.

1.38 A compound according to Embodiment 1.37 wherein R³ is selected fromhydrogen; fluorine; cyano; hydroxy; amino; and a C₁₋₆ non-aromatichydrocarbon group which is optionally substituted with one to sixfluorine atoms and wherein one, but not all, carbon atoms of thehydrocarbon group may optionally be replaced by a heteroatom selectedfrom O, N and S and oxidized forms thereof.

1.39 A compound according to Embodiment 1.38 wherein R³ is selected fromhydrogen; fluorine; cyano; hydroxy; amino; C₁₋₄ alkyl and C₁₋₄ alkoxy,wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy are each optionally substitutedwith one to six fluorine atoms.

1.40 A compound according to Embodiment 1.39 wherein R³ is selected fromhydrogen; fluorine; hydroxy and methoxy.

1.41 A compound according to Embodiment 1.40 wherein R³ is hydrogen.

1.42 A compound according to any one of Embodiments 1.1 to 1.41 whereinR⁴ is hydrogen or an acyclic C₁₋₆ hydrocarbon group.

1.43 A compound according to Embodiment 1.42 wherein R⁴ is hydrogen oran acyclic C₁₋₃ hydrocarbon group.

1.44 A compound according to Embodiment 1.43 wherein R⁴ is hydrogen or aC₁₋₃ alkyl group or a C₂₋₃ alkynyl group.

1.45 A compound according to Embodiment 1.44 wherein R⁴ is selected fromhydrogen, methyl, ethyl, ethynyl and 1-propynyl.

1.46 A compound according to Embodiment 1.45 wherein R⁴ is selected fromhydrogen and methyl.

1.47 A compound according to Embodiment 1.46 wherein R⁴ is methyl.

1.48 A compound according to any one of the preceding Embodimentswherein R⁵, when present, is a non-aromatic C₁₋₄ hydrocarbon groupoptionally substituted with one or more fluorine atoms; or a group offormula CH₂N(R^(a))OOR^(b).

1.49 A compound according to Embodiment 1.48 wherein the non-aromaticC₁₋₄ hydrocarbon group is a saturated C₁₋₄ hydrocarbon group.

1.50 A compound according to any one of Embodiments 1.1 to 1.49 whereinR⁵, when present, is hydrogen.

1.51 A compound according to any one of Embodiments 1.1 to 1.48 whereinR⁵, when present, is selected from hydrogen and a saturated C₁₋₄hydrocarbon group.

1.52 A compound according to Embodiment 1.51 wherein the saturated C₁₋₄hydrocarbon group is a C₁₋₄ alkyl group.

1.53 A compound according to Embodiment 1.52 wherein the saturated C₁₋₄hydrocarbon group is a C₁₋₃ alkyl group.

1.54 A compound according to Embodiment 1.53 wherein the C₁₋₃ alkylgroup is selected from methyl, ethyl and isopropyl.

1.55 A compound according to Embodiment 1.54 wherein the C₁₋₃ alkylgroup is ethyl.

1.56 A compound according to any one of the preceding Embodimentswherein R⁶, when present, is a non-aromatic C₁₋₄ hydrocarbon group.

1.57 A compound according to Embodiment 1.56 wherein the non-aromaticC₁₋₄ hydrocarbon group is a saturated C₁₋₄ hydrocarbon group.

1.58 A compound according to any one of Embodiments 1.1 to 1.54 whereinR⁶, when present, is hydrogen.

1.59 A compound according to Embodiment 1.57 wherein the saturated C₁₋₄hydrocarbon group is a C₁₋₃ alkyl group.

1.60 A compound according to Embodiment 1.59 wherein the C₁₋₃ alkylgroup is selected from methyl, ethyl and isopropyl.

1.61 A compound according to any one of the preceding Embodimentswherein R⁷, when present, is a non-aromatic C₁₋₄ hydrocarbon group.

1.62 A compound according to Embodiment 1.61 wherein the non-aromaticC₁₋₄ hydrocarbon group is a saturated C₁₋₄ hydrocarbon group.

1.63 A compound according to any one of Embodiments 1.1 to 1.60 whereinR⁷, when present, is hydrogen.

1.64 A compound according to any one of Embodiments 1.1 to 1.60 whereinR⁷, when present, is selected from hydrogen and a saturated C₁₋₄hydrocarbon group.

1.65 A compound according to Embodiment 1.62 or Embodiment 1.64 whereinthe saturated C₁₋₄ hydrocarbon group is a C₁₋₄ alkyl group.

1.66 A compound according to Embodiment 1.65 wherein the saturated C₁₋₄hydrocarbon group is a C₁₋₃ alkyl group.

1.67 A compound according to Embodiment 1.66 wherein the C₁₋₃ alkylgroup is selected from methyl, ethyl and isopropyl.

1.68 A compound according to any one of the preceding Embodimentswherein, when R¹ is an optionally substituted 5- or 6-membered ring, itis selected from aromatic rings containing 0, 1 or 2 or 3 heteroatomsselected from O, N and S and oxidized forms thereof.

1.69 A compound according to Embodiment 1.68 wherein the aromatic ringis carbocyclic.

1.70 A compound according to Embodiment 1.69 wherein the aromatic ringis heterocyclic.

1.71 A compound according to any one of Embodiments 1.1 to 1.67 wherein,when R¹ is an optionally substituted 5- or 6-membered ring, it isselected from non-aromatic rings containing 0, 1 or 2 or 3 heteroatomsselected from O, N and S and oxidized forms thereof.

1.72 A compound according to Embodiment 1.71 wherein the non-aromaticring is carbocyclic.

1.73 A compound according to Embodiment 1.72 wherein the non-aromaticring is heterocyclic.

1.74 A compound according to any one of Embodiments 1.68 to 1.73 whereinthe ring is a 5-membered ring.

1.75 A compound according to any one of Embodiments 1.68 to 1.73 whereinthe ring is a 6-membered ring.

1.76 A compound according to any one of the preceding Embodimentswherein, when R¹ is an optionally substituted 5- or 6-membered ring, itis substituted with 0, 1, 2 or 3 substituents R⁸.

1.77 A compound according to Embodiment 1.76 wherein there are 0, 1 or 2substituents R⁸ present.

1.78 A compound according to Embodiment 1.77 wherein there are 0substituents R⁸ present.

1.79 A compound according to Embodiment 1.77 wherein there is 1substituent R⁸ present.

1.80 A compound according to Embodiment 1.77 wherein there are 2substituents R⁸ present.

1.81 A compound according to any one of Embodiments 1.76, 1.77, 1.79,and 1.80 wherein R⁸ when present is selected from fluorine; cyano; oxo;hydroxy; OR⁵; NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; SR⁵; SOR⁵ andSO₂R⁵; and a C₁₋₆ non-aromatic hydrocarbon group which is optionallysubstituted with one to six fluorine atoms and wherein one or two, butnot all, carbon atoms of the hydrocarbon group may optionally bereplaced by a heteroatom selected from O, N and S and oxidized formsthereof.

1.82 A compound according to Embodiment 1.81 wherein R⁸ is selected fromfluorine; cyano; oxo; hydroxy; OR⁵; NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵ and SO₂R⁵;and a C₁₋₄ non-aromatic hydrocarbon group which is optionallysubstituted with one to six fluorine atoms and wherein one or two, butnot all, carbon atoms of the hydrocarbon group may optionally bereplaced by a heteroatom selected from O, N and S and oxidized formsthereof.

1.83 A compound according to Embodiment 1.82 wherein R⁸ is selected fromfluorine; cyano; oxo; hydroxy; OR⁵; NR⁵R⁶; and a C₁₋₄ non-aromatichydrocarbon group which is optionally substituted with one to sixfluorine atoms.

1.84 A compound according to Embodiment 1.83 wherein R⁸ is selected fromcyano; oxo; hydroxy; OR⁵; NR⁵R⁶; and C₁₋₄ alkyl.

1.85 A compound according to any one of Embodiments 1.1 to 1.84 whereinq is 0.

1.86 A compound according to any one of Embodiments 1.1 to 1.84 whereinq is 1.

1.87 A compound according to any one of Embodiments 1.1 to 1.84 whereinq is 2.

1.88 A compound according to any one of Embodiments 1.1 to 1.87 whereinr is 1.

1.89 A compound according to any one of Embodiments 1.1 to 1.88 whereins is 0.

1.90 A compound according to any one of Embodiments 1.1 to 1.88 whereinr is 1 and s is 1.

1.91 A compound according to any one of Embodiments 1.1 to 1.87 whereinr is 2 and s is 0.

1.92 A compound according to any one of Embodiments 1.1 to 1.891 whereinthe moiety:

is selected from groups A to F below:

1.92 A compound according to having the formula (2):

wherein Q is an optionally substituted 4 membered ring, and R⁴ is asdefined in any one of Embodiments 1.35 to 1.40.

1.93 A compound according to formula (2) wherein Q has one or moresubstituents, for example one, or two substituents which are selectedfrom (L)-R¹⁰, (L)-R¹¹ and (L)-R¹², where L is a bond or a CH₂ group;R¹⁰, R¹¹ and R¹² are independently selected from hydrogen; fluorine;chlorine; bromine; cyano; oxo; hydroxy; OR; NR¹⁵R¹⁶; COR¹⁵; CSR¹⁵;COOR¹⁵; COSR¹⁵; OCOR¹⁵; NR¹COR¹⁵; CONR¹⁵R¹⁶; CSNR¹⁵R¹⁶; NR¹⁷CONR¹⁵R¹⁶;R¹⁷COOR¹⁵; OCONR¹⁵R¹⁶; SR¹⁵; SOR¹⁵ and SO₂R¹⁵; a C₁₋₆ non-aromatichydrocarbon group which is optionally substituted with one to sixfluorine atoms and wherein one or two, but not all, carbon atoms of thehydrocarbon group may optionally be replaced by a heteroatom selectedfrom O, N and S and oxidized forms thereof; and an optionallysubstituted 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatomsselected from O, N and S and oxidized forms thereof;

-   -   wherein the optional substituents for the optionally substituted        5- or 6-membered ring are selected from a group R⁸ consisting of        hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR⁵;        NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶;        NR⁷COOR⁵; OCONR⁵R⁶; SR⁵; SOR⁵ and SO₂R⁵; and a C₁₋₆ non-aromatic        hydrocarbon group which is optionally substituted with one to        six fluorine atoms and wherein one or two, but not all, carbon        atoms of the hydrocarbon group may optionally be replaced by a        heteroatom selected from O, N and S and oxidized forms thereof;    -   wherein R¹⁵, R¹⁶ and R¹⁷ are the same or different, or may be        joined together to form a ring, and each is independently        selected from hydrogen, a non-aromatic C₁₋₆ hydrocarbon group        optionally substituted with one or more fluorine atoms and        wherein one or two, but not all, carbon atoms of the hydrocarbon        group may optionally be replaced by a heteroatom selected from        O, N and S and oxidized forms thereof; or a group of formula        CH₂N(R^(a))COOR^(b); or a group of formula (L)-R¹⁸ where L is a        bond or a CH₂ group and R¹⁸ is an optionally substituted 5- or        6-membered ring containing 0, 1, 2 or 3 heteroatoms selected        from O, N and S and oxidized forms thereof;    -   wherein the optional substituents for the optionally substituted        5- or 6-membered ring are selected from a group R⁸.

1.94 A compound according to Embodiments 1.1 to 1.93 having the formula(3):

wherein q, R¹, R² and R⁴ are as defined in any one preceding embodimentand the ring A is cyclobutyl or azetidine.

1.95 A compound according to Embodiment 1.94 wherein the ring A iscyclobutyl.

1.96 A compound according to Embodiment 1.95 wherein the ring A isazetidine.

1.97 A compound according to Embodiment 1.96 having the formula (4):

wherein q, R¹, R² and R⁴ are as defined in any one preceding Embodiment.

1.98 A compound according to Embodiment 1.1 which is as defined in anyone of Examples 1-1 to 1-7.

1.99 A compound according to any one of Embodiments 1.1 to 1.97 having amolecular weight of less than 550.

1.100 A compound according to Embodiment 1.99 having a molecular weightof less than 500.

1.101 A compound according to Embodiment 1.100 having a molecular weightof, or less than 450.

1.102 A compound according to any one of Embodiments 1.1 to 1.101 whichis in the form of a salt.

1.103 A compound according to Embodiment 1.102 wherein the salt is anacid addition salt.

1.104 A compound according to Embodiment 1.102 or Embodiment 1.103wherein the salt is a pharmaceutically acceptable salt.

Definitions

In this application, the following definitions apply, unless indicatedotherwise.

The term “treatment”, in relation to the uses of the compounds of theformula (1), is used to describe any form of intervention where acompound is administered to a subject suffering from, or at risk ofsuffering from, or potentially at risk of suffering from the disease ordisorder in question. Thus, the term “treatment” covers bothpreventative (prophylactic) treatment and treatment where measurable ordetectable symptoms of the disease or disorder are being displayed.

The term “effective therapeutic amount” as used herein (for example inrelation to methods of treatment of a disease or condition) refers to anamount of the compound which is effective to produce a desiredtherapeutic effect. For example, if the condition is pain, then theeffective therapeutic amount is an amount sufficient to provide adesired level of pain relief. The desired level of pain relief may be,for example, complete removal of the pain or a reduction in the severityof the pain.

The term “non-aromatic hydrocarbon group” as in “C₁₋₁₀ non-aromatichydrocarbon group” or “acyclic C₁₋₅ non-aromatic hydrocarbon group”refers to a group consisting of carbon and hydrogen atoms and whichcontains no aromatic rings. The hydrocarbon group may be fully saturatedor may contain one or more carbon-carbon double bonds or carbon-carbontriple bonds, or mixtures of double and triple bonds. The hydrocarbongroup may be a straight chain or branched chain group or may consist ofor contain a cyclic group. Thus the term non-aromatic hydrocarbonincludes alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenyl alkyl and so on.

The terms “alkyl”, “alkenyl”, “alkynyl”, “cycloalkyl” aryl, heteroaryland “cycloalkenyl” are used in their conventional sense (e.g. as definedin the IUPAC Gold Book) unless indicated otherwise.

The term “saturated hydrocarbon group” as in “C₁₋₄ saturated hydrocarbongroup” refers to a hydrocarbon group containing no carbon-carbon doublebonds or triple bonds. The saturated hydrocarbon group can therefore bean alkyl group, a cycloalkyl group, a cycloalkylalkyl group, analkylcycloalkyl group or a alkylcycloalkylalkyl group. Examples of C₁₋₄saturated hydrocarbon groups include C₁₋₄ alkyl groups, cyclopropyl,cyclobutyl and cyclopropylmethyl.

The term “cycloalkyl” as used herein, where the specified number ofcarbon atoms permits, includes both monocyclic cycloalkyl groups such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, andbicyclic and tricyclic groups. Bicyclic cycloalkyl groups includebridged ring systems such as bicycloheptane, bicyclooctane andadamantane.

In the definitions of R¹, R², R³ and R⁴ above, where stated, one or twobut not all, carbon atoms of the non-aromatic hydrocarbon group mayoptionally be replaced by a heteroatom selected from O, N and S and (inthe case of R¹ and R⁴) oxidised forms thereof. It will be appreciatedthat when a carbon atom is replaced by a heteroatom, the lower valenciesof the heteroatoms compared to carbon means that fewer atoms will bebonded to the heteroatoms than would have been bonded to the carbon atomthat has been replaced. Thus, for example, replacement of of a carbonatom (valency of four) in a CH₂ group by oxygen (valency of two) willmean that the resulting molecule will contain two less hydrogen atomsand replacement of a carbon atom (valency of four) in a CH₂ group bynitrogen (valency of three) will mean that the resulting molecule willcontain one less hydrogen atom.

Examples of a heteroatom replacements for carbon atoms includereplacement of a carbon atom in a —CH₂—CH₂—CH₂— chain with oxygen orsulfur to give an ether —CH₂—O—CH₂— or thioether —CH₂—S—CH₂—,replacement of a carbon atom in a group CH₂—C≡C—H with nitrogen to givea nitrile (cyano) group CH₂—C═N, replacement of a carbon atom in a group—CH₂—CH₂—CH₂— with C═O to give a ketone —CH₂—C(O)—CH₂—, replacement of acarbon atom in a group —CH₂—CH₂—CH₂— with S═O or SO₂ to give a sulfoxide—CH₂—S(O)—CH₂— or sulfone —CH₂—S(O)₂—CH₂—, replacement of a carbon atomin a —CH₂—CH₂—CH₂— chain with C(O)NH to give an amide —CH₂—CH₂—C(O)—NH—,replacement of a carbon atom in a —CH₂—CH₂—CH₂— chain with nitrogen togive an amine —CH₂—NH—CH₂—, and replacement of a carbon atom in a—CH₂—CH₂—CH₂— chain with C(O)O to give an ester (or carboxylic acid)—CH₂—CH₂—C(O)—O—. In each such replacement, at least one carbon atom ofthe hydrocarbon group must remain.

Salts

Many compounds of the formula (1) can exist in the form of salts, forexample acid addition salts or, in certain cases salts of organic andinorganic bases such as carboxylate, sulfonate and phosphate salts. Allsuch salts are within the scope of this invention, and references tocompounds of the formula (1) include the salt forms of the compounds asdefined in Embodiments 1.102 to 1.104.

The salts are typically acid addition salts.

The salts of the present invention can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods such as methods described in Pharmaceutical Salts: Properties,Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth(Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.Generally, such salts can be prepared by reacting the free acid or baseforms of these compounds with the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally, nonaqueousmedia such as ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are used.

Acid addition salts (as defined in Embodiment 1.120) may be formed witha wide variety of acids, both inorganic and organic. Examples of acidaddition salts falling within Embodiment 1.120 include mono- or di-saltsformed with an acid selected from the group consisting of acetic,2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic),L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric,ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic,fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic(e.g. D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric,glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric,hydriodic), isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic),lactobionic, maleic, malic, (−)-L-malic, malonic, (±)-DL-mandelic,methanesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic,1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic,palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic,salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric,tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic andvaleric acids, as well as acylated amino acids and cation exchangeresins.

Where the compounds of the formula (1) contain an amine function, thesemay form quaternary ammonium salts, for example by reaction with analkylating agent according to methods well known to the skilled person.Such quaternary ammonium compounds are within the scope of formula (1).

The compounds of the invention may exist as mono- or di-salts dependingupon the pKa of the acid from which the salt is formed.

The salt forms of the compounds of the invention are typicallypharmaceutically acceptable salts, and examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, saltsthat are not pharmaceutically acceptable may also be prepared asintermediate forms which may then be converted into pharmaceuticallyacceptable salts. Such non-pharmaceutically acceptable salts forms,which may be useful, for example, in the purification or separation ofthe compounds of the invention, also form part of the invention.

Stereoisomers

Stereoisomers are isomeric molecules that have the same molecularformula and sequence of bonded atoms but which differ only in thethree-dimensional orientations of their atoms in space. Thestereoisomers can be, for example, geometric isomers or optical isomers.

Geometric Isomers

With geometric isomers, the isomerism is due to the differentorientations of an atom or group about a double bond, as in cis andtrans (Z and E) isomerism about a carbon-carbon double bond, or cis andtrans isomers about an amide bond, or syn and anti isomerism about acarbon nitrogen double bond (e.g. in an oxime), or rotational isomerismabout a bond where there is restricted rotation, or cis and transisomerism about a ring such as a cycloalkane ring.

Accordingly, in another embodiment (Embodiment 1.121), the inventionprovides a geometric isomer of a compound according to any one ofEmbodiments 1.1 to 1.104.

Optical Isomers

Where compounds of the formula contain one or more chiral centres, andcan exist in the form of two or more optical isomers, references to thecompounds include all optical isomeric forms thereof (e.g. enantiomers,epimers and diastereoisomers), either as individual optical isomers, ormixtures (e.g. racemic mixtures) or two or more optical isomers, unlessthe context requires otherwise.

Accordingly, in another embodiment (Embodiment 1.132) the inventionprovides a compound according to any one of Embodiments 1.1 to 1.121which contains a chiral centre.

The optical isomers may be characterised and identified by their opticalactivity (i.e. as + and − isomers, or d and l isomers) or they may becharacterised in terms of their absolute stereochemistry using the “Rand S” nomenclature developed by Cahn, Ingold and Prelog, see AdvancedOrganic Chemistry by Jerry March, 4^(th) Edition, John Wiley & Sons, NewYork, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew.Chem. Int. Ed. Engl., 1966, 5, 385-415. Optical isomers can be separatedby a number of techniques including chiral chromatography(chromatography on a chiral support) and such techniques are well knownto the person skilled in the art. As an alternative to chiralchromatography, optical isomers can be separated by formingdiastereoisomeric salts with chiral acids such as (+)-tartaric acid,(−)-pyroglutamic acid, (−)-di-toluoyl-L-tartaric acid, (+)-mandelicacid, (−)-malic acid, and (−)-camphorsulphonic, separating thediastereoisomers by preferential crystallisation, and then dissociatingthe salts to give the individual enantiomer of the free base.

Where compounds of the invention exist as two or more optical isomericforms, one enantiomer in a pair of enantiomers may exhibit advantagesover the other enantiomer, for example, in terms of biological activity.Thus, in certain circumstances, it may be desirable to use as atherapeutic agent only one of a pair of enantiomers, or only one of aplurality of diastereoisomers.

Accordingly, in another embodiment (Embodiment 1.133), the inventionprovides compositions containing a compound according to Embodiment1.132 having one or more chiral centres, wherein at least 55% (e.g. atleast 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound ofEmbodiment 1.108 is present as a single optical isomer (e.g. enantiomeror diastereoisomer).

In one general embodiment (Embodiment 1.134), 99% or more (e.g.substantially all) of the total amount of the compound (or compound foruse) of Embodiment 1.132 is present as a single optical isomer.

For example, in one embodiment (Embodiment 1.135) the compound ispresent as a single enantiomer.

In another embodiment (Embodiment 1.136), the compound is present as asingle diastereoisomer.

The invention also provides mixtures of optical isomers, which may beracemic or non-racemic. Thus, the invention provides:

1.137 A compound according to Embodiment 1.132 which is in the form of aracemic mixture of optical isomers.

1.138 A compound according to Embodiment 1.132 which is in the form of anon-racemic mixture of optical isomers.

Isotopes

The compounds of the invention as defined in any one of Embodiments 1.1to 1.138 may contain one or more isotopic substitutions, and a referenceto a particular element includes within its scope all isotopes of theelement. For example, a reference to hydrogen includes within its scope¹H, ²H (D), and ³H (T). Similarly, references to carbon and oxygeninclude within their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and¹⁸O.

In an analogous manner, a reference to a particular functional groupalso includes within its scope isotopic variations, unless the contextindicates otherwise. For example, a reference to an alkyl group such asan ethyl group also covers variations in which one or more of thehydrogen atoms in the group is in the form of a deuterium or tritiumisotope, e.g. as in an ethyl group in which all five hydrogen atoms arein the deuterium isotopic form (a perdeuteroethyl group).

The isotopes may be radioactive or non-radioactive. In one embodiment ofthe invention (Embodiment 1.140), the compound of any one of Embodiments1.1 to 1.138 contains no radioactive isotopes. Such compounds arepreferred for therapeutic use. In another embodiment (Embodiment 1.141),however, the compound of any one of Embodiments 1.1 to 1.138 may containone or more radioisotopes. Compounds containing such radioisotopes maybe useful in a diagnostic context.

Solvates

Compounds of the formula (1) as defined in any one of Embodiments 1.1 to1.141 may form solvates. Preferred solvates are solvates formed by theincorporation into the solid state structure (e.g. crystal structure) ofthe compounds of the invention of molecules of a non-toxicpharmaceutically acceptable solvent (referred to below as the solvatingsolvent). Examples of such solvents include water, alcohols (such asethanol, isopropanol and butanol) and dimethylsulphoxide. Solvates canbe prepared by recrystallising the compounds of the invention with asolvent or mixture of solvents containing the solvating solvent. Whetheror not a solvate has been formed in any given instance can be determinedby subjecting crystals of the compound to analysis using well known andstandard techniques such as thermogravimetric analysis (TGE),differential scanning calorimetry (DSC) and X-ray crystallography. Thesolvates can be stoichiometric or non-stoichiometric solvates.Particularly preferred solvates are hydrates, and examples of hydratesinclude hemihydrates, monohydrates and dihydrates.

Accordingly, in further embodiments 1.150 and 1.151, the inventionprovides:

1.151 A compound according to any one of Embodiments 1.1 to 1.141 in theform of a solvate.

1.152 A compound according to Embodiment 1.151 wherein the solvate is ahydrate.

For a more detailed discussion of solvates and the methods used to makeand characterise them, see Bryn et al., Solid-State Chemistry of Drugs,Second Edition, published by SSCI, Inc of West Lafayette, Ind., USA,1999, ISBN 0-967-06710-3.

Alternatively, rather than existing as a hydrate, the compound of theinvention may be anhydrous. Therefore, in another embodiment (Embodiment1.153), the invention provides a compound as defined in any one ofEmbodiments 1.1 to 1.141 in an anhydrous form (e.g. anhydrouscrystalline form).

Crystalline and Amorphous Forms

The compounds of any one of Embodiments 1.1 to 1.153 may exist in acrystalline or non-crystalline (e.g. amorphous) state. Whether or not acompound exists in a crystalline state can readily be determined bystandard techniques such as X-ray powder diffraction (XRPD). Crystalsand their crystal structures can be characterised using a number oftechniques including single crystal X-ray crystallography, X-ray powderdiffraction (XRPD), differential scanning calorimetry (DSC) and infrared spectroscopy, e.g. Fourier Transform infra-red spectroscopy (FTIR).The behaviour of the crystals under conditions of varying humidity canbe analysed by gravimetric vapour sorption studies and also by XRPD.Determination of the crystal structure of a compound can be performed byX-ray crystallography which can be carried out according to conventionalmethods such as those described herein and as described in Fundamentalsof Crystallography, C. Giacovazzo, H. L. Monaco, D. Viterbo, F.Scordari, G. Gilli, G. Zanotti and M. Catti, (International Union ofCrystallography/Oxford University Press, 1992 ISBN 0-19-855578-4 (p/b),0-19-85579-2 (h/b)). This technique involves the analysis andinterpretation of the X-ray diffraction of single crystal. In anamorphous solid, the three dimensional structure that normally exists ina crystalline form does not exist and the positions of the moleculesrelative to one another in the amorphous form are essentially random,see for example Hancock et al. J. Pharm. Sci. (1997), 86, 1).

Accordingly, in further embodiments, the invention provides:

1.160 A compound according to any one of Embodiments 1.1 to 1.153 in acrystalline form.

1.161 A compound according to any one of Embodiments 1.1 to 1.153 whichis:

(a) from 50% to 100% crystalline, and more particularly is at least 50%crystalline, or at least 60% crystalline, or at least 70% crystalline,or at least 80% crystalline, or at least 90% crystalline, or at least95% crystalline, or at least 98% crystalline, or at least 99%crystalline, or at least 99.5% crystalline, or at least 99.9%crystalline, for example 100% crystalline.

1.162 A compound according to any one of Embodiments 1.1 to 1.153 whichis in an amorphous form.

Prodrugs

The compounds of the formula (1) as defined in any one of Embodiments1.1 to 1.162 may be presented in the form of a pro-drug. By “prodrugs”is meant for example any compound that is converted in vivo into abiologically active compound of the formula (1), as defined in any oneof Embodiments 1.1 to 1.162.

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). Duringmetabolism, the ester group (—C(═O)OR) is cleaved to yield the activedrug. Such esters may be formed by esterification, for example, of anyhydroxyl groups present in the parent compound with, where appropriate,prior protection of any other reactive groups present in the parentcompound, followed by deprotection if required.

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). Forexample, the prodrug may be a sugar derivative or other glycosideconjugate, or may be an amino acid ester derivative.

Accordingly, in another embodiment (Embodiment 1.170), the inventionprovides a pro-drug of a compound as defined in any one of Embodiments1.1 to 1.170 wherein the compound contains a functional group which isconvertable under physiological conditions to form a hydroxyl group oramino group.

Complexes and Clathrates

Also encompassed by formula (1) in Embodiments 1.1 to 1.170 arecomplexes (e.g. inclusion complexes or clathrates with compounds such ascyclodextrins, or complexes with metals) of the compounds of Embodiments1.1 to 1.170.

Accordingly, in another embodiment (Embodiment 1.180), the inventionprovides a compound according to any one of Embodiments 1.1 to 1.170 inthe form of a complex or clathrate.

Biological Activity and Therapeutic Uses

The compounds of the present invention have activity as muscarinic M₁and/or M₄ receptor agonists. The muscarinic activity of the compoundscan be determined using the Phospho-ERK1/2 assay described in Example Abelow.

A significant advantage of compounds of the invention is that they arehighly selective for the M₁ and/or M₄ receptor relative to the M₂ and M₃receptor subtypes.

Compounds of the invention are not agonists of the M₂ and M₃ receptorsubtypes. For example, whereas compounds of the invention typically havepEC₅₀ values of at least 6 (preferably at least 6.5) and E_(max) valuesof greater than 80 (preferably greater than 95) against the M₁ and/or M₄receptor in the functional assay described in Example A, they may havepEC₅₀ values of less than 5 and E_(max) values of less than 20% whentested against the M₂ and M₃ subtypes in the functional assay of ExampleA.

Accordingly, in Embodiments 2.1 to 2.9, the invention provides:

2.1 A compound according to any one of Embodiments 1.1 to 1.180 for usein medicine.

2.2 A compound according to any one of Embodiments 1.1 to 1.180 for useas a muscarinic M₁ and/or M₄ receptor agonist.

2.3 A compound according to any one of Embodiments 1.1 to 1.180 which isa muscarinic M₁ receptor agonist having a pEC₅ in the range from 6.0 to7.5 and an E_(max) of at least 90 against the M₁ receptor in the assayof Example A herein or an assay substantially similar thereto.

2.4 A compound according to Embodiment 2.3 which is a muscarinic M₁receptor agonist having a pEC₅₀ in the range from 6.5 to 7.5.

2.5 A compound according to Embodiment 2.3 or Embodiment 2.4 having anE_(max) of at least 95 against the M₁ receptor.

2.6 A compound according to any one of Embodiments 1.1 to 1.180 which isa muscarinic M₄ receptor agonist having a pEC₅ in the range from 6.0 to8.0 and an E_(max) of at least 90 against the M₄ receptor in the assayof Example A herein or an assay substantially similar thereto.

2.7 A compound according to Embodiment 2.6 which is a muscarinic M₄receptor agonist having a pEC₅₀ in the range from 6.5 to 8.0.

2.8 A compound according to Embodiment 2.6 or Embodiment 2.7 having anE_(max) of at least 95 against the M₄ receptor.

2.9 A compound according to any one of Embodiments 2.3 to 2.8 which isselective for the M₁ and/or M₄ receptor compared to the muscarinic M₂and M₃ receptors.

2.10 A compound according to Embodiment 2.9 which is selective for theM₁ receptor compared to the muscarinic M₂ and M₃ receptors.

2.11 A compound according to Embodiment 2.9 which is selective for theM₄ receptor compared to the muscarinic M₂ and M₃ receptors.

2.12 A compound according to any one of Embodiments 2.3 to 2.5 which isselective for the M₁ receptor compared to the muscarinic M₂, M₃ and M₄receptors.

2.13 A compound according to any one of Embodiments 2.6 to 2.8 which isselective for the M₄ receptor compared to the muscarinic M₁, M₂ and M₃receptors.

2.14 A compound according to any one of Embodiments 2.3 to 2.8 which isselective for the M₁ and M₄ receptor compared to the muscarinic M₂ andM₃ receptors.

2.15 A compound according to any one of Embodiments 2.3 to 2.14 whichhas a pEC₅₀ of less than 5 and an E_(max) of less than 50 against themuscarinic M₂ and M₃ receptor subtypes.

2.16 A compound according to Embodiment 2.15 which has a pEC₅₀ of lessthan 4.5 and/or an E_(max) of less than 30 against the muscarinic M₂ andM₃ receptor subtypes.

2.17 A compound according to any one of Embodiments 1.1 to 1.180 andEmbodiments 2.3 to 2.16 for use in the treatment of a disease orcondition mediated by the muscarinic M₁ receptor.

By virtue of their muscarinic M₁ and/or M₄ receptor agonist activity,compounds of the invention can be used in the treatment of Alzheimer'sdisease, schizophrenia and other psychotic disorders, cognitivedisorders and other diseases mediated by the muscarinic M₁ and/or M₄receptor, and can also be used in the treatment of various types ofpain.

Accordingly, in Embodiments 2.18 to 2.37, the invention provides:

2.18 A compound according to any one of Embodiments 1.1 to 1.180 for usein the treatment of a cognitive disorder or psychotic disorder.

2.19 A compound for use in according to Embodiment 2.18 wherein thecognitive disorder or psychotic disorder comprises, arises from or isassociated with a condition selected from cognitive impairment, MildCognitive Impairment, frontotemporal dementia, vascular dementia,dementia with Lewy bodies, presenile dementia, senile dementia,Friederich's ataxia, Down's syndrome, Huntington's chorea, hyperkinesia,mania, Tourette's syndrome, Alzheimer's disease, progressivesupranuclear palsy, impairment of cognitive functions includingattention, orientation, learning disorders, memory (i.e. memorydisorders, amnesia, amnesic disorders, transient global amnesia syndromeand age-associated memory impairment) and language function; cognitiveimpairment as a result of stroke, Huntington's disease, Pick disease,Aids-related dementia or other dementia states such as Multiinfarctdementia, alcoholic dementia, hypotiroidism-related dementia, anddementia associated to other degenerative disorders such as cerebellaratrophy and amyotropic lateral sclerosis; other acute or sub-acuteconditions that may cause cognitive decline such as delirium ordepression (pseudodementia states) trauma, head trauma, age relatedcognitive decline, stroke, neurodegeneration, drug-induced states,neurotoxic agents, age related cognitive impairment, autism relatedcognitive impairment, Down's syndrome, cognitive deficit related topsychosis, and post-electroconvulsive treatment related cognitivedisorders; cognitive disorders due to drug abuse or drug withdrawalincluding nicotine, cannabis, amphetamine, cocaine, Attention DeficitHyperactivity Disorder (ADHD) and dyskinetic disorders such asParkinson's disease, neuroleptic-induced parkinsonism, and tardivedyskinesias, schizophrenia, schizophreniform diseases, psychoticdepression, mania, acute mania, paranoid, hallucinogenic and delusionaldisorders, personality disorders, obsessive compulsive disorders,schizotypal disorders, delusional disorders, psychosis due tomalignancy, metabolic disorder, endocrine disease or narcolepsy,psychosis due to drug abuse or drug withdrawal, bipolar disorders,epilepsy and schizo-affective disorder.

2.20 A compound according to any one of Embodiments 1.1 to 1.180 for usein the treatment of Alzheimer's disease.

2.21 A compound according to any one of Embodiments 1.1 to 1.180 for usein the treatment of Schizophrenia.

2.22 A compound according to any one of Embodiments 1.1 to 1.180 for usein the treatment of Alzheimer's disease and/or dementia with Lewybodies.

2.23 A method of treatment of a cognitive disorder in a subject (e.g. amammalian patient such as a human, e.g. a human in need of suchtreatment), which method comprises the administration of atherapeutically effective dose of a compound according to any one ofEmbodiments 1.1 to 1.180.

2.24 A method according to Embodiment 2.20 wherein the cognitivedisorder comprises, arises from or is associated with a condition asdefined in Embodiment 2.19.

2.25 A method according to Embodiment 2.24 wherein the cognitivedisorder arises from or is associated with Alzheimer's disease.

2.26 A method according to Embodiment 2.24 wherein the cognitivedisorder is Schizophrenia.

2.27 The use of a compound according to any one of Embodiments 1.1 to1.180 for the manufacture of a medicament for the treatment of acognitive disorder.

2.28 The use according to Embodiment 2.27 wherein the cognitive disordercomprises, arises from or is associated with a condition as defined inEmbodiment 2.11.

2.29 The use according to Embodiment 2.28 wherein the cognitive disorderarises from or is associated with Alzheimer's disease.

2.30 The use according to Embodiment 2.28 wherein the cognitive disorderis Schizophrenia.

2.31 A compound according to any one of Embodiments 1.1 to 1.180 for thetreatment or lessening the severity of acute, chronic, neuropathic, orinflammatory pain, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpetic neuralgia, general neuralgias, visceral pain,osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, or cancer pain.

2.32 A method of treatment or lessening the severity of acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, or cancer pain, which method comprises theadministration of a therapeutically effective dose of a compoundaccording to any one of Embodiments 1.1 to 1.180.

2.33 A compound according to any one of Embodiments 1.1 to 1.180 for thetreatment of peripheral disorders such as reduction of intra ocularpressure in Glaucoma and treatment of dry eyes and dry mouth includingSjogren's Syndrome.

2.34 A method of treatment of peripheral disorders such as reduction ofintra ocular pressure in Glaucoma and treatment of dry eyes and drymouth including Sjogren's Syndrome, which method comprises theadministration of a therapeutically effective dose of a compoundaccording to any one of Embodiments 1.1 to 1.180.

2.35 The use of a compound according to any one of Embodiments 1.1 to1.180 for the manufacture of a medicament for the treatment or lesseningthe severity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, visceral pain, osteoarthritis pain,postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica,back pain, head or neck pain, severe or intractable pain, nociceptivepain, breakthrough pain, postsurgical pain, or cancer pain or for thetreatment of peripheral disorders such as reduction of intra ocularpressure in Glaucoma and treatment of dry eyes and dry mouth includingSjogren's Syndrome.

2.36 The use of a compound according to any one of Embodiments 1.1 to1.180 for the treatment of addiction.

2.37 The use of a compound according to any one of Embodiments 1.1 to1.180 for the treatment of movement disorders such as Parkinson'sdisease, ADHD, Huntingdon's disease, tourette's syndrome and othersyndromes associated with dopaminergic dysfunction as an underlyingpathogenetic factor driving disease.

Methods for the Preparation of Compounds of the Formula (1)

Compounds of the formula (1) can be prepared in accordance withsynthetic methods well known to the skilled person and as describedherein.

Accordingly, in another embodiment (Embodiment 3.1), the inventionprovides a process for the preparation of a compound as defined in anyone of Embodiments 1.1 to 1.180, which process comprises:

(A) the reaction of a compound of the formula (10)

with a compound of the formula (11):

under reductive amination conditions; wherein R¹, R², R³, R⁴ and Q areas defined in any one of Embodiments 1.1 to 1.180; or

(B) the reaction of a compound of the formula (12):

with a compound of the formula Cl—C(═O)—CH₂—R⁴, in the presence of abase; or

(C) the reaction of a compound of the formula (10)

with a compound of the formula (13):

under nucleophilic substitution conditions; wherein R¹, R², R³, R⁴ and Qare as defined in any one of Embodiments 1.1 to 1.180; and optionally:

(D) converting one compound of the formula (1) to another compound ofthe formula (1).

In process variant (A), the piperidine heterocycle (10) is reacted withthe substituted ketone (11) under reductive amination conditions. Thereductive amination reaction is typically carried out at ambienttemperature using a borohydride reducing agent such as sodiumtriacetoxy-borohydride in a solvent such as dichloromethane ordichloroethane containing acetic acid.

In process variant (C), the piperidine heterocycle (10) is reacted withthe sulfonic ester (13, R=methyl, trifluoromethyl or 4-methylphenyl) ina nucleophilic substitution reaction which is typically carried out withmild heating (e.g. to a temperature of from about 40° C. to about 70°C.) either neat, with no solvent, or in a suitable solvent such astetrahydrofuran, acetonitrile or dimethylacetamide.

Intermediate compounds of the formula (12) can be prepared by the seriesof reactions shown in Scheme 1 below.

In reaction Scheme 1, the piperidine heterocycle (10) is reacted withthe Boc-protected spiroketone (14) under reductive amination conditions.The reductive amination reaction is typically carried out with mildheating (e.g. to a temperature of from about 40° C. to about 70° C.) inthe presence of either sodium cyanoborohydride in combination with zincchloride or sodium triacetoxyborohydride in combination with titaniumisopropoxide in a solvent such as dichloromethane or dichloroethanecontaining acetic acid to give an intermediate piperidine compound (15)which is then deprotected by removal of the Boc group by treatment withacid (e.g. trifluoroacetic acid in dichloromethane) to give the compound(12).

Compounds of the formula (12) can also be prepared by the sequence ofreactions shown in Scheme 2 below.

In Scheme 2, the Boc-protected spiroketone (14) is reduced to thealcohol (16) using sodium borohydride in methanol. The alcohol (16) isthen activated as the sulfonic ester (17, R=methyl, trifluoromethyl or4-methylphenyl) using the corresponding sulfonyl chloride indichloromethane in the presence of a tertiary amine such astriethylamine or N,N-diisopropylethylamine. The sulfonic ester (17) isreacted with the piperidine heterocycle (10) in a nucleophilicsubstitution reaction which is typically carried out with mild heating(e.g. to a temperature of from about 40° C. to about 70° C.) eitherneat, with no solvent, or in a suitable solvent such as tetrahydrofuran,acetonitrile or dimethylacetamide to give compound (15) which is thendeprotected by removal of the Boc group by treatment with acid (e.g.trifluoroacetic acid in dichloromethane) to give the compound (12).

Once formed, one compound of the formula (1), or a protected derivativethereof, can be converted into another compound of the formula (1) bymethods well known to the skilled person. Examples of syntheticprocedures for converting one functional group into another functionalgroup are set out in standard texts such as Advanced Organic Chemistryand Organic Syntheses (see references above) or Fiesers' Reagents forOrganic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser(ISBN: 0-471-58283-2). Examples of these transformations include amidebond formation, urea formation, carbamate formation, alkylationreactions, N-arylation reaction and C—C bond coupling reactions.

In many of the reactions described above, it may be necessary to protectone or more groups to prevent reaction from taking place at anundesirable location on the molecule. Examples of protecting groups, andmethods of protecting and deprotecting functional groups, can be foundin Protective Groups in Organic Synthesis (T. Greene and P. Wuts; 3rdEdition; John Wiley and Sons, 1999).

Compounds made by the foregoing methods may be isolated and purified byany of a variety of methods well known to those skilled in the art andexamples of such methods include recrystallisation and chromatographictechniques such as column chromatography (e.g. flash chromatography) andHPLC.

Pharmaceutical Formulations

While it is possible for the active compound to be administered alone,it is preferable to present it as a pharmaceutical composition (e.g.formulation).

Accordingly, in another embodiment (Embodiment 4.1) of the invention,there is provided a pharmaceutical composition comprising at least onecompound of the formula (1) as defined in any one of Embodiments 1.1 to1.180 together with at least one pharmaceutically acceptable excipient.

In one embodiment (Embodiment 4.2), the composition is a tabletcomposition.

In another embodiment (Embodiment 4.3), the composition is a capsulecomposition.

The pharmaceutically acceptable excipient(s) can be selected from, forexample, carriers (e.g. a solid, liquid or semi-solid carrier),adjuvants, diluents (e.g solid diluents such as fillers or bulkingagents; and liquid diluents such as solvents and co-solvents),granulating agents, binders, flow aids, coating agents,release-controlling agents (e.g. release retarding or delaying polymersor waxes), binding agents, disintegrants, buffering agents, lubricants,preservatives, anti-fungal and antibacterial agents, antioxidants,buffering agents, tonicity-adjusting agents, thickening agents,flavouring agents, sweeteners, pigments, plasticizers, taste maskingagents, stabilisers or any other excipients conventionally used inpharmaceutical compositions.

The term “pharmaceutically acceptable” as used herein means compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof a subject (e.g. a human subject) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each excipient mustalso be “acceptable” in the sense of being compatible with the otheringredients of the formulation.

Pharmaceutical compositions containing compounds of the formula (1) canbe formulated in accordance with known techniques, see for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., USA.

The pharmaceutical compositions can be in any form suitable for oral,parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic,otic, rectal, intra-vaginal, or transdermal administration.

Pharmaceutical dosage forms suitable for oral administration includetablets (coated or uncoated), capsules (hard or soft shell), caplets,pills, lozenges, syrups, solutions, powders, granules, elixirs andsuspensions, sublingual tablets, wafers or patches such as buccalpatches.

Tablet compositions can contain a unit dosage of active compoundtogether with an inert diluent or carrier such as a sugar or sugaralcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugarderived diluent such as sodium carbonate, calcium phosphate, calciumcarbonate, or a cellulose or derivative thereof such as microcrystallinecellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, and starches such as corn starch. Tablets may also containsuch standard ingredients as binding and granulating agents such aspolyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymerssuch as crosslinked carboxymethylcellulose), lubricating agents (e.g.stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT),buffering agents (for example phosphate or citrate buffers), andeffervescent agents such as citrate/bicarbonate mixtures. Suchexcipients are well known and do not need to be discussed in detailhere.

Tablets may be designed to release the drug either upon contact withstomach fluids (immediate release tablets) or to release in a controlledmanner (controlled release tablets) over a prolonged period of time orwith a specific region of the GI tract.

The pharmaceutical compositions typically comprise from approximately 1%(w/w) to approximately 95%, preferably % (w/w) active ingredient andfrom 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient(for example as defined above) or combination of such excipients.Preferably, the compositions comprise from approximately 20% (w/w) toapproximately 90% (w/w) active ingredient and from 80% (w/w) to 10% of apharmaceutically excipient or combination of excipients. Thepharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, pre-filled syringes, dragées, powders,tablets or capsules.

Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5%lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/or bulking agents(depending on drug dose).

They may also contain 0-10% (w/w) polymer binders, 0-5% (w/w)antioxidants, 0-5% (w/w) pigments. Slow release tablets would inaddition typically contain 0-99% (w/w) release-controlling (e.g.delaying) polymers (depending on dose). The film coats of the tablet orcapsule typically contain 0-10% (w/w) polymers, 0-3% (w/w) pigments,and/or 0-2% (w/w) plasticizers.

Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50%(w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI)(depending on dose and if freeze dried). Formulations for intramusculardepots may also contain 0-99% (w/w) oils.

The pharmaceutical formulations may be presented to a patient in“patient packs” containing an entire course of treatment in a singlepackage, usually a blister pack.

The compounds of the formula (1) will generally be presented in unitdosage form and, as such, will typically contain sufficient compound toprovide a desired level of biological activity. For example, aformulation may contain from 1 nanogram to 2 grams of active ingredient,e.g. from 1 nanogram to 2 milligrams of active ingredient. Within theseranges, particular sub-ranges of compound are 0.1 milligrams to 2 gramsof active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50milligrams to 500 milligrams), or 1 microgram to 20 milligrams (forexample 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2milligrams of active ingredient).

For oral compositions, a unit dosage form may contain from 1 milligramto 2 grams, more typically 10 milligrams to 1 gram, for example 50milligrams to 1 gram, e.g. 100 miligrams to 1 gram, of active compound.

The active compound will be administered to a patient in need thereof(for example a human or animal patient) in an amount sufficient toachieve the desired therapeutic effect (effective amount). The preciseamounts of compound administered may be determined by a supervisingphysician in accordance with standard procedures.

EXAMPLES

The invention will now be illustrated, but not limited, by reference tothe specific embodiments described in the following examples.

Examples 1-1 to 1-9

The compounds of Examples 1-1 to 1-9 shown in Table 1 below have beenprepared. Their NMR and LCMS properties and the methods used to preparethem are set out in Table 3.

TABLE 1

Example 1-1

Example 1-2

Example 1-3

Example 1-4

Example 1-5

Example 1-6

Example 1-7

General Procedures

Where no preparative routes are included, the relevant intermediate iscommercially available. Commercial reagents were utilized withoutfurther purification. Room temperature (rt) refers to approximately20-27° C. ¹H NMR spectra were recorded at 400 MHz on either a Bruker orJeol instrument. Chemical shift values are expressed in parts permillion (ppm), i.e. (δ:)-values. The following abbreviations are usedfor the multiplicity of the NMR signals: s=singlet, br=broad, d=doublet,t=triplet, q=quartet, quint=quintet, td=triplet of doublets, tt=tripletof triplets, qd=quartet of doublets, ddd=doublet of doublet of doublets,ddt=doublet of doublet of triplets, m=multiplet. Coupling constants arelisted as J values, measured in Hz. NMR and mass spectroscopy resultswere corrected to account for background peaks. Chromatography refers tocolumn chromatography performed using 60-120 mesh silica gel andexecuted under nitrogen pressure (flash chromatography) conditions. TLCfor monitoring reactions refers to TLC run using the specified mobilephase and Silica gel F254 (Merck) as a stationary phase.Microwave-mediated reactions were performed in Biotage Initiator or CEMDiscover microwave reactors.

LCMS experiments were typically carried out using electrosprayconditions as specified for each compound under the followingconditions:

LCMS Method A: Instruments: Waters 2695, Photo Diode Array, ZQ-2000Detector; Column: X-Bridge C18, 3.5 micron, 150×4.6 mm; Gradient [time(min)/solvent B in A (%)]: 0.00/5, 5.00/90, 5.80/95, 10/95; Solvents:solvent A=0.1% ammonia in H₂O; solvent B=0.1% ammonia in MeCN; Injectionvolume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to 1000 AMU(+ve electrospray); column at ambient temperature; Flow rate 1.0 mL/min.

LCMS Method B:

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column:X-Bridge C18, 3.5 micron, 50×4.6 mm; Gradient [time (min)/solvent B in A(%)]: 0.01/0, 0.20/0, 5.00/90, 5.80/95, 7.20/95, 7.21/100, 10.00/100;Solvents: solvent A=0.1% ammonia in H₂O; solvent B=0.1% ammonia in MeCN;Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to1000 AMU (+ve electrospray); column at ambient temperature; Flow rate1.0 mL/min.

LCMS Method C

Instruments: Agilent 1260 Infinity LC with Diode Array Detector, Agilent6120B Single Quadrupole MS with API-ES Source; Column: PhenomenexGemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time (min)/solvent B in A(%)]: Method: 0.00/5, 2.00/95, 2.50/95, 2.60/5, 3.00/5; Solvents:solvent A=2.5 L H₂O+2.5 mL of (28% NH₃ in H₂O); solvent B=2.5 L MeCN+129mL H₂O+2.7 mL of (28% NH₃ in H₂O); Injection volume 0.5 μL; UV detection190 to 400 nM; column temperature 40° C.; Flow rate 1.5 mL/min.

LCMS Methods D and E

Instruments: HP 1100 with G1315A DAD, Micromass ZQ; Column: WatersX-Bridge C-18, 2.5 micron, 2.1×20 mm or Phenomenex Gemini-NX C-18, 3micron, 2.0×30 mm; Gradient [time (min)/solvent D in C (%)]: Method D:0.00/2, 0.10/2, 2.50/95, 3.50/95, 3.55/2, 4.00/2 or Method E: 0.00/2,0.10/2, 8.40/95, 9.40/95, 9.50/2, 10.00/2; Solvents: solvent C=2.5 LH₂O+2.5 mL 28% ammonia in H₂O solution; solvent D=2.5 L MeCN+135 mLH₂O+2.5 mL 28% ammonia in H₂O solution); Injection volume 1 μL; UVdetection 230 to 400 nM; Mass detection 130 to 800 AMU (+ve and −veelectrospray); column temperature 45° C.; Flow rate 1.5 mL/min.

LCMS data in the experimental section are given in the format: Mass ion,retention time, UV activity.

Abbreviations

-   AcOH=acetic acid-   CDI=1,1′-Carbonyldiimidazole-   d=day(s)-   DAST=diethylaminosulfur trifluoride-   DCE=dichloroethane-   DCM=dichloromethane-   DIPEA=diisopropylethylamine-   DIAD=diisopropyl azodicarboxylate-   DMF=dimethylformamide-   DMP=Dess-Martin periodinane-   DMSO=dimethylsulfoxide-   ES=electro spray ionisation-   EtOAc=ethyl acetate-   h=hour(s)-   HATU=1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate-   HPLC=high performance liquid chromatography-   LC=liquid chromatography-   LiAlH₄/LAH=Lithium aluminium hydride-   MeCN=acetonitrile-   MeOH=methanol-   min=minute(s)-   MS=mass spectrometry-   Et₃N=triethylamine-   NMR=nuclear magnetic resonance-   rt=room temperature-   sat.=saturated-   sol.=solution-   STAB=sodium triacetoxyborohydride-   THE=tetrahydrofuran-   TLC=thin layer chromatography-   Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal,    secondary, iso, and tertiary.

General Synthetic Procedures for Intermediates: Route 1 Procedure forthe Preparation of Intermediate 2, ethyl2-oxo-6-azaspiro[3.4]octane-6-carboxylate

6-Boc-2-oxo-6-azaspiro[3.4]octane (3.37 g, 15 mmol) was addedportionwise to hydrogen chloride (4 M dioxane solution, 50 mL, 210mmol). Caution: effervescence. After 24 h, the reaction was concentratedin vacuo and the residual solid was dissolved in a mixture of Et₃N (4.18ml, 30 mmol) and DCM (66 mL). On completion of dissolution, the solutionwas immediately cooled to 0° C., then ethyl chloroformate (1.57 mL, 16.5mmol) was added dropwise. After 18 h, the mixture was poured intodichloromethane (100 mL) and NaHCO₃ (aq) (100 mL) and extracted (2×100mL). The organic layers were collected, washed with brine (20 mL), driedover MgSO₄, then the residue after evaporation was purified by columnchromatography (normal phase, [Biotage SNAP cartridge KP-sil 100 g,40-63 μm, 60 Å, 50 mL per min, gradient 0% to 4% MeOH in DCM]) to giveIntermediate 2, ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (2.47 g,83%) as a colourless oil. The data for the title compound are in Table2.

Route 2 Procedure for the Preparation of Intermediate 8,(4S)-4-ethyl-1-(piperidin-4-yl)azetidin-2-one

To a solution of MeOH (60 mL) at −10° C. was added thionyl chloride(1.25 mL, 17.1 mmol) dropwise, and the resulting mixture stirred at −10°C. for 1 h. (3S)-3-Aminopentanoic acid (1.0 g, 8.5 mmol) was then addedin one portion and the resulting mixture stirred at rt for 20 h. Thesolvent was removed in vacuo to yield methyl (3S)-3-aminopentanoate.HCl(1.69 g) as a light brown oil, which was used crude in the next step.

LC/MS (method C): m/z 132 (M+H)+ (ES+), at 0.56 min, UV inactive.

To methyl (3S)-3-aminopentanoate.HCl (250 mg, assumed 1.3 mmol) in DMF(15 mL) was added DIPEA (1.30 mL, 7.5 mmol), AcOH (0.13 mL, 2.3 mmol),tert-butyl 4-oxopiperidine-1-carboxylate (297 mg, 1.5 mmol) and sodiumtriacetoxyborohydride (632 mg, 3.0 mmol) and the resulting mixturestirred at rt for 24 h. The solvent was then removed in vacuo and theresidue purified on silica (Biotage Isolera, SNAP 25 g cartridge, 0-10%0.7 M NH₃ in MeOH/DCM) and relevant fractions combined to yieldtert-butyl4-{[(3S)-1-methoxy-1-oxopentan-3-yl]amino}piperidine-1-carboxylate (1.14g) as a yellow oil, which crystallized upon standing at rt to a whitesolid, and was used crude in the next step.

LC/MS (method C): m/z 315 (M+H)+ (ES+), at 1.40 min, UV active.

To a solution of crude tert-butyl4-{[(3S)-1-methoxy-1-oxopentan-3-yl]amino}piperidine-1-carboxylate (1.14g, assumed 1.3 mmol) in THE (30 mL) was added LiOH (313 mg, 7.5 mmol)and H₂O(7.5 mL) and the mixture stirred at rt for 65 h. The mixture wasthen heated to reflux for 2 h before addition of further LiOH (313 mg,7.5 mmol) and heating at reflux for an additional 2 h. Volatiles werethen removed in vacuo, and the aqueous layer acidified to pH 3 with 1 Maq. HCl and extracted with EtOAc. The aqueous layer was concentrated invacuo to a colourless oil which was purified on silica (Biotage Isolera,SNAP 50 g cartridge, 0.7 M NH₃ in MeOH/DCM, 4:1) to yield(3S)-3-{[1-(tert-butoxycarbonyl)piperidin-4-yl]amino}pentanoic acid(0.91 g) as a white powder, which was used crude in the next step.

LC/MS (method C): m/z 301 (M+H)+ (ES+), at 0.62 min, UV active.

Tert-butyl4-{[(3S)-1-methoxy-1-oxopentan-3-yl]amino}piperidine-1-carboxylate (624mg, assumed 0.9 mmol), 1-methyl-2-chloropyridinium iodide (584 mg, 2.3mmol) and Et₃N (0.64 mL, 4.6 mmol) in MeCN (40 mL) were heated to refluxfor 22 h. The mixture was purified on silica (Biotage isolera, SNAP 50 gcartridge, EtOAc/isohexane, 1,1 to 100% EtOAc over 5 CV and then 100%EtOAc over 10 CV) to yield tert-butyl4-[(2S)-2-ethyl-4-oxoazetidin-1-yl]piperidine-1-carboxylate (194 mg,80%) as a colourless oil.

LC/MS (method C): m/z 305 (M+Na)+ (ES+), at 1.26 min, UV active.

To tert-butyl4-[(2S)-2-ethyl-4-oxoazetidin-1-yl]piperidine-1-carboxylate (194 mg, 0.7mmol) in DCM (3 mL) was added TFA (3 mL) and the mixture stirred at rtfor 30 min. The solvent was removed in vacuo to yield intermediate 8,(4S)-4-ethyl-1-(piperidin-4-yl)azetidin-2-one TFA salt (374 mg) as abrown oil, which was used crude in the next step. The data for the titlecompound are in table 2.

Route 3 Procedure for the Preparation of Intermediate 9,4-(3,3-difluoroazetidin-1-yl)piperidine

A solution of 3,3-difluoroazetidine hydrochloride (300 mg, 2.3 mmol),tert-butyl 4-oxopiperidine-1-carboxylate (461 mg, 2.3 mmol) and DIPEA(0.40 mL, 2.3 mmol) in DMF (6 mL) was heated to 50° C. for 16 h beforecooling to rt, addition of sodium triacetoxyborohydride (1.23 g, 5.8mmol) and AcOH (0.13 mL, 2.3 mmol) and further heating at 40° C. for 16h. The mixture was cooled to rt, quenched by addition of sat. aq. NaHCO₃(3 mL) and concentrated in vacuo. The residue was diluted with DCM (15mL) and washed with sat. aq. NaHCO₃ (15 mL) and brine (15 mL). Organicswere dried (Biotage phase separator) and concentrated in vacuo. Thecrude residue was purified on silica (Biotage Isolera, SNAP 25 gcartridge, 0-10% MeOH/DCM and subsequently SNAP 25 g cartridge, 0-5%MeOH/DCM) to yield tert-butyl4-(3,3-difluoroazetidin-1-yl)piperidine-1-carboxylate (273 mg, 43%) as awhite crystalline solid, which was used directly in the next step.

To tert-butyl 4-(3,3-difluoroazetidin-1-yl)piperidine-1-carboxylate (273mg, 1.0 mmol) in DCM (8 mL) at 0° C. was added TFA (2 mL) and themixture stirred at rt for 16 h. The reaction mixture was thenconcentrated in vacuo to yield intermediate 9,4-(3,3-difluoroazetidin-1-yl)piperidine. 2TFA as a pink oil, which wasused directly in the next step. The data for the title compound are intable 2.

Step 1: Alternative Work Up Procedure

The reaction was treated with H₂O(0.5 mL) and concentrated in vacuo. Thecrude residue was applied directly to a 25 g SNAP chromatographycartridge and eluted with a gradient 0-10% MeOH/DCM (Biotage Isolera).

Route 4 Procedure for the Preparation of Intermediate 15,1-(piperidin-4-yl)azetidin-2-one.TFA

To tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g, 25.1 mmol) in MeOH(50 mL) was added methyl 3-aminopropanoate (3.5 g, 25.1 mmol) and Et₃N(10.7 mL, 75.3 mmol) and the reaction mixture stirred at 50° C. for 7 h.The mixture was then cooled to rt, followed by addition of NaBH₃CN (4.75g, 75.1 mmol) portionwise and further stirring at rt for 17 h. Thesolvent was then removed in vacuo and the residue partitioned betweenH₂O (250 mL) and EtOAc (200 mL). The layers were separated and theaqueous layer extracted with EtOAc (2×200 mL). Combined organics weredried (Na₂SO₄), the solvent was removed in vacuo and the residue waspurified by column chromatography (normal basic activated alumina,10-13% EtOAc/hexane) to give tert-butyl4-((3-methoxy-3-oxopropyl)amino)piperidine-1-carboxylate (3.30 g, 47%)as a yellow gum.

LC/MS (method A): m/z 287 (M+H)+ (ES+), at 3.82 min, UV active.

To a solution of tert-butyl 4-((3-methoxy-3-oxopropyl) amino)piperidine-1-carboxylate (2.0 g, 7.0 mmol) in THE (20 mL) was addedmethyl magnesium bromide (3.5 mL, 10.5 mmol) dropwise at 0° C., and theresulting mixture stirred at rt for 50 h. The reaction was quenched withsat. aq. NH₄Cl, the solvent removed in vacuo and the residue partitionedbetween H₂O (150 mL) and EtOAc (120 mL). The layers were separated andthe aqueous layer further extracted with EtOAc (2×120 mL). Combinedorganics were dried (Na₂SO₄), the solvent removed in vacuo and theresidue purified by column chromatography (normal basic activatedalumina, 8-10% EtOAc/hexane) to give tert-butyl4-(2-oxoazetidin-1-yl)piperidine-1-carboxylate (600 mg, 35%) as a yellowgum.

LC/MS (method B): m/z 255 (M+H)+ (ES+), at 3.63 min, UV active.

To tert-butyl 4-(2-oxoazetidin-1-yl) piperidine-1-carboxylate (600 mg,2.4 mmol) in DCM (5 mL) at 0° C. was added trifluoroacetic acid (0.4 mL,4.7 mmol) dropwise and the resulting mixture stirred at rt for 8 h. Thesolvent was then removed in vacuo and the residue purified bytrituration with ether (3×2 mL) to give Intermediate 15,1-(piperidin-4-yl) azetidin-2-one.TFA (510 mg, 81%) as a yellow gum. Thedata for the title compound are in table 2.

General Synthetic Procedures for Examples Route a Typical Procedure forthe Preparation of Piperidines Via Reductive Amination, as Exemplifiedby the Preparation of Example 1-1 Ethyl2-[4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

A solution of crude 4-(3,3-difluoroazetidin-1-yl)piperidine (assumed 1.0mmol), ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (183 mg, 0.9mmol) and DIPEA (0.34 mL, 2.0 mmol) in DMF (6 mL) was stirred at 40° C.for 2 h. The solution was cooled to rt before addition of sodiumtriacetoxyborohydride (522 mg, 2.5 mmol) and AcOH (60 μL, 1.0 mmol) andfurther stirring at 40° C. for 16 h. The solvent was removed in vacuoand the residue diluted with sat. aq. NaHCO₃ (15 mL) and extracted withDCM (2×15 mL). Combined organics were dried (Biotage phase separatorcartridge) and concentrated in vacuo. The crude residue was purified onsilica (Biotage Isolera, SNAP 25 g cartridge, 0-10% MeOH/DCM) andsubsequently by prep HPLC [reverse phase (Gemini-NX, C18, 5μ, 100×30mm), 30 mL per min, gradient 30% (0.3 min), then 30-60% (over 8.7 min),then 60% (for 0.5 min), then 60-100% (over 0.2 min), then 100% (for 1min), then 30% (for 0.8 min), MeCN/0.2% NH₃ in water] to yield ethyl2-[4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylateisomer 1 (29 mg, 9%) as a colourless oil and Example 1-1, ethyl2-[4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylateisomer 2 (30 mg, 9%) as a colourless oil. The data for the titlecompound are in table 3

Route a Alternative Work Up Procedure

The reaction was allowed to cool to rt, treated with H₂O (0.5 mL) andconcentrated in vacuo.

The crude residue was applied directly to a 10 g SNAP chromatographycartridge and eluted with a gradient 0-10% MeOH/DCM (Biotage Isolera).Relevant fractions were combined and further purified by reverse phaseprep HPLC.

Route b Typical Procedure for the Preparation of Piperidines ViaReductive Amination, as Exemplified by the Preparation of Example 1-3ethyl2-[4-(2-oxoazetidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

A solution of 1-(piperidin-4-yl) azetidin-2-one.TFA (200 mg, 0.8 mmol),ethyl 2-oxo-6-azaspiro [3.4] octane-6-carboxylate (254 mg, 1.3 mmol) andEt₃N (0.6 mL, 3.9 mmol) in MeOH (10 mL) was stirred at 55° C. for 5 h.The reaction mixture was then cooled to 0° C. before addition of NaBH₃CN(246 mg, 3.9 mmol) portionwise and further stirring at 25° C. for 17 h.The solvent was removed in vacuo, the residue partitioned between H₂O(100 mL) and DCM (80 mL) and the layers separated. The aqueous layer wasextracted with DCM (2×80 mL) and combined organics dried (Na₂SO₄) andthe solvent removed in vacuo. The residue was purified by prep HPLC[reverse phase (X-BRIDGE C-18, 150×9 mm, 5 μm), 17 mL per min, gradient20% (over 30.0 min), 100% (over 2.0 min), then 20% (over 2.0 min), 0.1%NH₃ in MeCN/water] to give ethyl2-(4-(2-oxoazetidin-1-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateisomer-1 (45 mg, 18%) as a yellow gum and Example 1-3, ethyl2-(4-(2-oxoazetidin-1-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateisomer-2 (28 mg, 11%) as a yellow gum. The data for the title compoundare in table 3.

Route c Typical Procedure for the Preparation of Piperidines ViaReductive Amination, as Exemplified by the Preparation of Example 1-5,ethyl2-{4-[(2S)-2-ethyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

To crude(4S)-4-ethyl-1-(piperidin-4-yl)azetidin-2-one TFA salt (374 mg,assume 0.7 mmol) in DMF(5 mL) was added DIPEA (0.60 mL, 3.4 mmol), AcOH(60 μL, 1.1 mmol), ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (136mg, 0.7 mmol) and sodium triacetoxyborohydride (437 mg, 2.1 mmol) andthe mixture stirred at rt for 65 h. The reaction mixture wasconcentrated to remove DMF and the residue purified on silica (BiotageIsolera, SNAP 25 cartridge, 0-10% 0.7 NH₃ in MOH/DCM over 10 CV) toyield a mixture of two isomers as a yellow residue. This was furtherpurified by prep HPLC [reverse phase (Gemini-NX, 18, 5μ, 100×30 mm), 30mL per min, gradient 30%(0.3 min), then 30-60% (over 8.7 min), then 60%(for 0.5 min), then 60-100% (over 0.2 min), then 100% (for 1 min), then30% (for 0.8 min), MeCN/0.2% NH₃ in water] to yield ethyl2-4-[(2S)-2-ethyl-4-oxoazetidin-1-yl]piperidin-1-yl-6-azaspiro[3.4]octane-6-carboxylateisomer (100 mg, 40%) as a gum and Example 1-5, ethyl2-{4-[(2S)-2-ethyl-4-oxoazetidin-1-yl}piperidin-1-yl-6-azaspiro[3.4]octane-6-carboxylateisomer 2 (76 mg, 30%) a gum. The data for the title compound are intable 3.

TABLE 2 Characterising data and commercial sources for startingmaterials and intermediates Inter- mediate Route Name Data 16-Boc-2-oxo-6- Commercially available, azaspiro[3.4]octane CAS:203661-71-6 2 Route 1 and Ethyl 2-oxo-6- ¹H NMR: (400 MHz, CDCl₃) δ:1.27 intermediates 1 azaspiro[3.4]octane-6- (t, J = 7.0 Hz, 3H), 2.08(t, J = 6.2 Hz, and 5 carboxylate 2 H), 2.94-3.17 (m, 4 H), 3.49-3.59(m, 4 H), 4.15 (q, J = 7.0 Hz, 2 H) 3 Route 1 and Methyl 2-oxo-6- ¹HNMR: (400 MHz, CD₃OD) δ:: 2.06- intermediates 1 azaspiro[3.4]octane-6-2.15 (m, 2 H), 2.94 - 3.04 (m, 2 H), and 4 carboxylate 3.05-3.17 (m, 2H), 3.47 (td, J = 6.8, 2.5 Hz, 2 H), 3.54 (d, J = 2.5 Hz, 2 H), 3.69 (s,3 H) 4 Methyl chloroformate Commercially available, CAS: 79-22-1 5 Ethylchloroformate Commercially available, CAS: 541-41-3 6(3S)-3-Aminopentanoic acid Commercially available. CAS: 14389-77-6 7Tert-butyl 4-oxopiperidine-1- Commercially available. carboxylate CAS:79099-07-3 8 Route 2 and (4S)-4-Ethyl-1-(piperidin-4- m/z 183 (M + H)+(ES+) intermediates 6 yl)azetidin-2-one.TFA and 7 9 Route 3 and4-(3,3-Difluoroazetidin-1- R_(f) = 0.10 (MeOH/DCM, 1:9) intermediates 7yl)piperidine. 2TFA and 10 10 3,3-Difluoroazetidine Commerciallyavailable. hydrochloride CAS: 288315-03-7 11 (R)-Methyl-2-azetidineCommercially available carboxylate.HCl CAS: 647854-63-5 12 Route 3 withMethyl (2R)-1-(piperidin-4- R_(f) = 0 (MeOH/DCM, 1:9) step 2 HClyl)azetidine-2- instead of TFA. carboxylate.2HCl Intermediates 7 and 1113 Methyl β-alaninate Commercially available. CAS: 4138-35-6 14 MeMgBrCommercially available. CAS: 75-16-1 15 Route 4 and1-(piperidin-4-yl)azetidin-2- (LC/MS method A) m/z 155 (M + H)⁺intermediates 7 one.TFA (ES⁺) at 1.87 min, UV active and 13 16 Route 2and (4R)-4-Ethyl-1-(piperidin-4- (LC/MS method D) m/z 183 (M + H)⁺intermediates 7 yl)azetidin-2-one.TFA (ES⁺) at 1.29 min, UV active and17 17 (3R)-3-Aminopentanoic acid Commercially available. CAS:131347-76-7 18 Route 2 and (4R)-4-methyl-1-(piperidin-4- m/z 169 (M +H)⁺ (ES⁺) intermediates 7 yl)azetidin-2-one and 19 19(3R)-3-aminobutanoic acid Commercially available. CAS: 3775-73-3 20Route 2 and (4S)-4-methyl-1-(piperidin-4- m/z 169 (M + H)⁺ (ES⁺)intermediates 7 yl)azetidin-2-one and 21 21 (3S)-3-aminobutanoic acidCommercially available. CAS: 3775-72-2

TABLE 3 Ex. Inter- Synthetic LCMS LCMS No. Name mediate method ¹H NMRMethod data 1-1 Isomer 2: Ethyl 2-[4-(3,3- 2 and 9 Route a (400 MHz,DMSO-d₆) δ: 1.13 (t, J = E m/z 358 (M + H)⁺difluoroazetidin-1-yl)piperidin- 7.0 Hz, 3 H), 1.57-1.60 (ES⁺) at1-yl]-6-azaspiro[3.4]octane-6- (m, 2 H), 1.70-1.82 (m, 6 H), 1.91-1.96(m, 2 H), 3.20 min, UV carboxylate 2.53-2.64 (m, 3 H), 2.03-2.14 (m, 1H), 3.10-3.26 inactive (m, 6 H), 3.48 (t, J = 12.5 Hz, 4 H), 3.96 (q, J= 7.0 Hz, 2 H) 1-2 Isomer 2: Ethyl 2-{4-[(2R)-2- 2 and 12 Route a (400MHz, DMSO-d₆) δ: 0.99-1.15 (m, 5 H), 1.47- E m/z 380 (M + H)⁺(methoxycarbonyl)azetidin-1- with 2.14 (m, 13 H), 2.53-2.65 (m, 2 H),2.81 (q, (ES⁺) at yl]piperidin-1-yl}-6- alternative J = 8.0 Hz, 1 H),3.11-3.27 (m, 6 H), 3.58 (s, 3 H), 5.41 min, UV azaspiro[3.4]octane-6-work up 3.67 (t, J = 8.0 Hz, 1 H), 3.97 (q, J = 7.0 Hz, 2 H) activecarboxylate procedure 1-3 Isomer 2: Ethyl 2-[4-(2- 2 and 15 Route b (400MHz, CDCl₃) δ: 1.22-1.30 (m, 3 H), 1.66- A m/z 336 (M + H)⁺oxoazetidin-1-yl)piperidin-1- 2.54 (m, 12 H), 2.66-3.03 (m, 5 H),3.21-3.68 (m, (ES⁺) at yl]-6-azaspiro[3.4]octane-6- 7 H), 4.08-4.19 (m,2 H) 3.30 min, UV carboxylate active 1-4 Isomer 2: Ethyl 2-{4-[(2S)-2- 2and 20 Route c (400 MHz, CDCl₃) δ: 1.19-1.22 (m, 3 H), 1.33 (d,methyl-4-oxoazetidin-1- J = 6.0 Hz, 3 H), 1.56-1.91 (m, 10 H), 1.97-2.07(m, yl]piperidin-1-yl}-6- 2 H), 2.41 (dd, J = 14.5, 2.0 Hz, 1 H),2.57-2.69 (m, E m/z 350 (M + H)⁺ azaspiro[3.4]octane-6- 1 H), 2.76-2.90(m, 2 H), 2.97 (dd, J = 14.5, 5.0 Hz, (ES⁺) at carboxylate 1 H), 3.23(d, J = 20.5 Hz, 2 H), 3.35 (dt, J = 20.0, 3.38 min, UV 6.5 Hz, 2 H),3.46-3.58 (m, 1 H), 3.68-3.75 active (m, 1 H), 4.07 (q, J = 7.0 Hz, 2 H)1-5 Isomer 2: Ethyl 2-{4-[(2S)-2- 2 and 8 Route c (400 MHz, CDCl₃) δ:0.89 (t, J = 7.0 Hz, E m/z 364 (M + H)⁺ ethyl-4-oxoazetidin-1- 3 H),1.24 (t, J = 6.5 (ES⁺) at yl]piperidin-1-yl}-6- Hz, 3 H), 1.39-1.50 (m,1 H), 1.55 -2.16 (m, 13 H), 3.77 min, UV azaspiro[3.4]octane-6- 2.48 (d,J = 7.0 Hz, 1 H), 2.56-2.71 (m, 1 H), 2.76- active carboxylate 2.94 (m,3 H), 3.24-3.43 (m, 4 H), 3.48-3.64 (m, 2 H), 4.10 (q, J = 7.0 Hz, 2 H)1-6 Isomer 2: Ethyl 2-{4-[(2R)-2- 2 and 18 Route c (400 MHz, CDCl₃) δ:1.20-1.25 (m, 3 H), 1.34 (d, E m/z 350 (M + H)⁺ methyl-4-oxoazetidin-1-J = 6.0 Hz, 3 H), 1.57-2.09 (m, 10 H), 2.30-3.59 (ES⁺) atyl]piperidin-1-yl}-6- (m, 12 H), 3.66-3.77 (m, 1 H), 4.05-4.17 (m, 2 H)3.38 min, UV azaspiro[3.4]octane-6- active carboxylate 1-7 Isomer 2:Ethyl 2-{4-[(2R)-2- 2 and 16 Route c (400 MHz, CDCl₃) δ: 0.85-0.92 (m, 3H), 1.19-1.25 E m/z 364 (M + H)⁺ ethyl-4-oxoazetidin-1- (m, 3 H),1.37-1.48 (m, 1 H), 1.56-2.07 (m, 11 H), (ES⁺) at yl]piperidin-1-yl}-6-2.43-3.55 (m, 13 H), 4.05-4.17 (m, 2 H) 3.73 min, UVazaspiro[3.4]octane-6- active carboxylate

Biological Activity Example A Phospho-ERK1/2 Assays

Functional assays were performed using the Alphascreen Surefirephospho-ERK1/2 assay (Crouch & Osmond, Comb. Chem. High ThroughputScreen, 2008). ERK1/2 phosphorylation is a downstream consequence ofboth Gq/11 and Gi/o protein coupled receptor activation, making ithighly suitable for the assessment of M₁, M₃ (Gq/11 coupled) and M₂, M₄receptors (Gi/o coupled), rather than using different assay formats fordifferent receptor subtypes. CHO cells stably expressing the humanmuscarinic M₁, M₂, M₃ or M₄ receptor were plated (25K/well) onto 96-welltissue culture plates in MEM-alpha+10% dialysed FBS. Once adhered, cellswere serum-starved overnight. Agonist stimulation was performed by theaddition of 5 μL agonist to the cells for 5 min (37° C.). Media wasremoved and 50 μL of lysis buffer added. After 15 min, a 4 μL sample wastransferred to 384-well plate and 7 μL of detection mixture added.Plates were incubated for 2 h with gentle agitation in the dark and thenread on a PHERAstar plate reader.

pEC₅₀ and E_(max) figures were calculated from the resulting data foreach receptor subtype.

The results are set out in Table 4 below.

For each example with the 4-5 spiro system two diastereomers exist whichhave been separated, unless stated otherwise, and assigned based ontheir retention time on LCMS analytical trace. In most examples, isomer1 is not active. Analytical data for active isomers is reported in Table3. Data for several weakly active compounds are included in Table 4 tohighlight preference of absolute stereochemistry.

TABLE 4 Muscarinic Activity pEC₅₀ M₁ pEC₅₀ M₂ pEC₅₀ M₃ pEC₅₀ M₄ (% Emaxcf. (% Emax cf. (% Emax cf. (% Emax cf. Ex. No. ACh) ACh) ACh) ACh) ACh  8.3 (102)    7.8 (105)   8.1 (115) 8.1 (110) 1-1 Isomer 2   6.0 (24)NT NT 6.8 (26) 1-2 Isomer 2 <4.7 (37)  <4.7 (7) <4.7 (7) 7.2 (67) 1-3Isomer 2 <4.7 (20) NT NT 6.7 (23) 1-4 Isomer 2 <4.7 (18) NT NT 6.8 (41)1-5 Isomer 2   6.5 (69)  <4.7 (37) <4.7 (0) 7.0 (56) 1-6 Isomer 2 <4.7(13) NT NT 6.6 (74) 1-7 Isomer 2   6.1 (94)   *6.3 (26) <4.7 (21) 7.1(101) *-variable results, NT - Not tested

Example B Pharmaceutical Formulations (i) Tablet Formulation

A tablet composition containing a compound of the formula (1) isprepared by mixing 50 mg of the compound with 197 mg of lactose (BP) asdiluent, and 3 mg magnesium stearate as a lubricant and compressing toform a tablet in known manner.

(ii) Capsule Formulation

A capsule formulation is prepared by mixing 100 mg of a compound of theformula (1) with 100 mg lactose and optionally 1% by weight of magnesiumstearate and filling the resulting mixture into standard opaque hardgelatin capsules.

EQUIVALENTS

The foregoing examples are presented for the purpose of illustrating theinvention and should not be construed as imposing any limitation on thescope of the invention. It will readily be apparent that numerousmodifications and alterations may be made to the specific embodiments ofthe invention described above and illustrated in the examples withoutdeparting from the principles underlying the invention. All suchmodifications and alterations are intended to be embraced by thisapplication.

1. A method for the treatment of a cognitive disorder or psychoticdisorder in a subject or for the treatment or lessening the severity ofacute, chronic, neuropathic, or inflammatory pain in a subject or forthe treatment of addiction in a subject, or for the treatment ofmovement disorders in a subject, comprising administering to the subjectan effective amount of a compound of the formula (1):

or a salt thereof, wherein q is 1; r is 1 or 2; s is 0 or 1 where thetotal of r and s is 1 or 2; Q is an azetidine linked to the adjacentsix-membered ring by the nitrogen atom of the azetidine ring; R¹ isselected from hydrogen; methyl; ethyl; fluorine; oxo; and COOMe; R^(2′)and R^(2″) are independently selected from hydrogen; fluorine; and aC₁₋₆ non-aromatic hydrocarbon group; R³ is hydrogen; R⁴ is hydrogen or aC₁₋₆ non-aromatic hydrocarbon group which is optionally substituted withone to six fluorine atoms and the dotted line indicates a single bond.2. The method according to claim 1, wherein R⁴ is selected from hydrogenand methyl.
 3. The method according to claim 1, wherein the compound isselected from the group consisting of: Ethyl2-[4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-2-(methoxycarbonyl)azetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(2-oxoazetidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-2-methyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-2-ethyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-2-methyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-2-ethyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;or a salt thereof.
 4. The method according to claim 1, wherein thecompound is a pharmaceutically acceptable salt of a compound as definedin claim
 1. 5. The method according to claim 1, wherein the compound isadministered to the subject as in the form of a pharmaceuticalcomposition comprising the compound as defined in claim 1 and apharmaceutically acceptable excipient.
 6. The method according to claim1 wherein the moiety:

is selected from:


7. The method according to claim 1 wherein the moiety:

is selected from:


8. The method according to claim 1, wherein the disorder is Alzheimer'sDisease, dementia with Lewy bodies or schizophrenia.
 9. The methodaccording to claim 1, wherein the disorder is Alzheimer's Disease. 10.The method according to claim 1, wherein the disorder is dementia withLewy bodies.
 11. The method according to claim 1, wherein the disorderis schizophrenia.